3-pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission

ABSTRACT

Novel 3-pyridyloxymethyl heterocyclic ether compounds of the formula: ##STR1## or the pharmaceutically-acceptable salts or prodrugs thereof are selective and potent ligands at neuronal nicotinic cholinergic channel receptors, and are effective in controlling synaptic transmission.

TECHNICAL FIELD

This invention relates to 3-pyridyloxymethyl heterocyclic ether compounds which control chemical synaptic transmission; to therapeutically-effective pharmaceutical compositions of these compounds; and to the use of said compositions to selectively control synaptic transmission.

BACKGROUND OF THE INVENTION

Compounds that selectively control chemical synaptic transmission offer therapeutic utility in treating disorders that are associated with dysfunctions in synaptic transmission. This utility may arise from controlling either pre-synaptic or post-synaptic chemical transmission. The control of synaptic chemical transmission is, in turn, a direct result of a modulation of the excitability of the synaptic membrane. Presynaptic control of membrane excitability results from the direct effect an active compound has upon the organelles and enzymes present in the nerve terminal for synthesizing, storing, and releasing the neurotransmitter, as well as the process for active re-uptake. Postsynaptic control of membrane excitability results from the influence an active compound has upon the cytoplasmic organelles that respond to neurotransmitter action.

An explanation of the processes involved in chemical synaptic transmission will help to illustrate more fully the potential applications of the invention. (For a fuller explanation of chemical synaptic transmission refer to Hoffman et al., "Neurotransmission: The autonomic and somatic motor nervous systems." In: Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 9th ed., J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. Goodman Gilman, eds., Pergamon Press, New York, 1996, pp. 105-139).

Typically, chemical synaptic transmission begins with a stimulus that depolarizes the transmembrane potential of the synaptic junction above the threshold that elicits an all-or-none action potential in a nerve axon. The action potential propagates to the nerve terminal where ion fluxes activate a mobilization process leading to neurotransmitter secretion and "transmission" to the postsynaptic cell. Those cells which receive communication from the central and peripheral nervous systems in the form of neurotransmitters are referred to as "excitable cells." Excitable cells are cells such as nerves, smooth muscle cells, cardiac cells and glands. The effect of a neurotransmitter upon an excitable cell may be to cause either an excitatory or an inhibitory postsynaptic potential (EPSP or IPSP, respectively) depending upon the nature of the postsynaptic receptor for the particular neurotransmitter and the extent to which other neurotransmitters are present. Whether a particular neurotransmitter causes excitation or inhibition depends principally on the ionic channels that are opened in the postsynaptic membrane (i.e., in the excitable cell).

EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na⁺ and K⁺), whereas IPSPs are the result of stabilization or hyperpolarization of the membrane excitability due to a increase in permeability to primarily smaller ions (including K⁺ and Cl⁻). For example, the neurotransmitter acetylcholine excites at skeletal muscle junctions by opening permeability channels for Na⁺ and K⁺. At other synapses, such as cardiac cells, acetylcholine can be inhibitory, primarily resulting from an increase in K⁺ conductance.

The biological effects of the compounds of the present invention result from modulation of a particular subtype of acetylcholine receptor. It is, therefore, important to understand the differences between two receptor subtypes. The two distinct subfamilies of acetylcholine receptors are defined as nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. (See Goodman and Gilman's, The Pharmacological Basis of Therapeutics, op. cit.).

The responses of these receptor subtypes are mediated by two entirely different classes of second messenger systems. When the nicotinic acetylcholine receptor is activated, the response is an increased flux of specific extracellular ions (e.g. Na⁺, K⁺ and Ca⁺⁺) through the neuronal membrane. In contrast, muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and inositol phosphates. Thus, the biological consequences of nicotinic acetylcholine receptor-activation are distinct from those of muscarinic receptor activation. In an analogous manner, inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are distinct and different from those arising from muscarinic receptor inhibition.

As indicated above, the two principal sites to which drug compounds that affect chemical synaptic transmission may be directed are the presynaptic nerve terminal and the postsynaptic membrane. Actions of drugs directed to the presynaptic site may be mediated through presynaptic receptors that respond to the neurotransmitter which the same secreting structure has released (i.e., an autoreceptor), or through a presynaptic receptor that responds to another neurotransmitter (i.e., a heteroreceptor). Actions of drugs directed to the postsynaptic membrane mimic the action of the endogenous neurotransmitter or inhibit the interaction of the endogenous neurotransmitter with a postsynaptic receptor.

Classic examples of drugs that modulate postsynaptic membrane excitability are the neuromuscular blocking agents which interact with nicotinic acetylcholine-gated channel receptors on skeletal muscle, for example, competitive (stabilizing) agents, such as curare, or depolarizing agents, such as succinylcholine.

In the central nervous system, postsynaptic cells can have many neurotransmitters impinging upon them. This makes it difficult to know the precise net balance of chemical synaptic transmission required to control a given cell. Nonetheless, by designing compounds that selectively affect only one pre- or postsynaptic receptor, it is possible to modulate the net balance of all the other inputs. Obviously, the more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders.

Knowing how specific neurotransmitters act in the CNS allows one to speculate about the disorders that may be treatable with certain CNS-active drugs. For example, dopamine is widely recognized as an important neurotransmitter in the central nervous systems in humans and animals. Many aspects of the pharmacology of dopamine have been reviewed by Roth and Elsworth, "Biochemical Pharmacology of Midbrain Dopamine Neurons", In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds., Raven Press, New York, 1995, pp 227-243). Patients with Parkinson's disease have a primary loss of dopamine containing neurons of the nigrostriatal pathway, which results in profound loss of motor control. Therapeutic strategies to replace the dopamine deficiency with dopamine mimetics, as well as administering pharmacologic agents that modify dopamine release and other neurotransmitters have been found to have therapeutic benefit ("Parkinson's Disease", In: Psychopharmacology: The Fourth Generation of Progress, op. cit, pp 1479-1484).

New and selective neurotransmitter controlling agents are still being sought, in the hope that one or more will be useful in important, but as yet poorly controlled, disease states or behavior models. For example, dementia, such as is seen with Alzheimer's disease or Parkinsonism, remains largely untreatable. Symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does the behavioral disorder Attention-Deficit Disorder (ADD). Specific agents for treatment of these and related disorders are few in number or non-existent.

A more complete discussion of the possible utility as CNS-active agents of compounds with activity as cholinergic ligands selective for neuronal nicotinic receptors, (i.e., for controlling chemical synaptic transmission) may be found in U.S. Pat. No. 5,472,958, to Gunn et al., issued Dec. 5, 1995, which is incorporated herein by reference.

Existing acetylcholine channel agonists are therapeutically sub-optima in treating the conditions discussed above. For example, such compounds have unfavorable pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability and tolerability (e.g., nicotine). In addition, other agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lachrymation, defecation and tachycardia (Benowitz et al., in: Nicotine Psychopharmacology, S. Wonnacott, M. A. H. Russell, & I. P. Stoleman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson, et at., in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336).

Various heterocyclic 2-pyrrolidinyloxy-substituted compounds with analgesic and hypotensive activities have been disclosed by Scheffier et al. (U.S. Pat. No. 4,643,995) and Tomioka et al. (Chem. Pharm. Bull, 38:2133-5, 1990).

Certain other 2-pyridyloxy-substituted compounds are disclosed inter alia by Engel et al. in U.S. Pat. No. 4,946,8345 as having analgesic activity.

Various other compounds having a pyrrolidine or azetidine moiety substituted at the 3-position with a heterocycloxy group have also been disclosed (cf. U.S. Pat. No. 4,592,866 to A. D. Cale; U.S. Pat. No. 4,705,853 to A. D. Cale; U.S. Pat. No. 4,956,359 to Taylor et al.; and U.S. Pat. No. 5,037,841 to Schoehe et al. and European patent application EP296560A2, to Sugimoto et al.).

Certain nicotine-related compounds having utility in enhancing cognitive function have been reported by Lin in U.S. Pat. No. 5,278,176, issued Jan. 11, 1994. Also, 2-(nitro)phenoxy compounds with similar funtion have been reported by Gunn et al., U.S. Pat. No. 5,472,958, issued Dec. 5, 1995.

In the PCT Patent Application WO94 08992 of Abreo et al., published Apr. 28, 1994, are disclosed, inter alia, various 3-pyridyloxy-heterocyclic compounds that are either unsubstituted or mono-substituted on the pyridine ring with groups such as Br, Cl, F, hydroxyl, C₁ -C₃ -alkyl or C₁ -C₃ -alkoxy, such compounds also described as having utility in enhancing cognitive function.

SUMMARY OF THE INVENTION

In accordance with the principal embodiment of the present invention, there is provided a class of 5-substituted 3-pyridyloxymethyl heterocyclic ether compounds which are selective and potent neuronal nicotinic cholinergic compounds useful in controlling synaptic transmission.

The compounds of the present invention are represented by formula (I): ##STR2## or a pharmaceutically acceptable salt thereof wherein n is selected from 1, 2 or 3.

The substituents R¹ is selected from the group consisting of hydrogen, allyl, and alkyl of one to six carbon atoms.

R² is selected from the group consisting of hydrogen, fluorine, chlorine, vinyl, and phenyl.

The linking group, L, is absent or is selected from the group consisting of alkylene of one to six carbon atoms, --C.tbd.C--, .paren open-st.CH═CH.paren close-st._(p) where p is one or two, ##STR3## where M is selected from --CH₂ --, and --NH--.

The substituent R³ is selected from the group consisting of a) hydrogen, b) alkyl of one to six carbon atoms, c) haloalkyl of one to six carbon atoms, d) hydroxyalkyl of one to six carbon atoms, e) alkoxy of one to six carbon atoms, f) amino, g) alkylamino of one to six carbon atoms, h) dialkylamino in which the two alkyl groups are independently of one to six carbon atoms, i) phenyl, j) naphthyl, k) biphenyl, l) furyl, m) thienyl, n) pyridinyl, o) pyrazinyl, p) pyridazinyl, q) pyrimidinyl, r) pyrrolyl, s) pyrazolyl, t) imidazolyl, u) indolyl, v) thiazolyl, w) oxazolyl, x) isoxazolyl, y) thiadiazolyl, z) oxadiazolyl, aa) quinolinyl, bb) isoquinolinyl, and cc) any of i) through bb) above substituted with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one tosix carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl in which the alkoxy and alkyl portions are independently of one to six carbon atoms, alkoxyalkoxyl in which the alkoxy portions are independently of one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms.

The above definitions of the various linking and substituent groups in the compounds of the present invention are limited by the provisos that i) when L is absent, R³ may not be hydrogen, alkyl of one to six carbon atoms, amino, alkylamino or dialkylamino; ii) when L is absent and R³ is hydrogen, R² is selected from vinyl, unsubstituted phenyl, and phenyl substituted as defined in bb) above; iii) when L is alkylene, R³ may not be hydrogen or alkyl; iv) when L is ##STR4## then R³ is selected from alkyl of one to six carbon atoms, i), j), l), m), n), q), r), and bb) as defined above, and any of i), j), l), m), n), q), r) and bb) as substituted as defined in cc) above; v) when L is ##STR5## and M is --CH₂ --, then R³ may not be hydrogen; and vi) f) through y) above may be substituted as defined in z) above by no more than one alkylamino, carboxyl, or alkoxycarbonyl substituent.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention there are provided a class of substituted azetidine compounds of Formula (I) above wherein n is 1.

In another embodiment of the invention there are provided a class of substituted pyrrolidine compounds of Formula (I) above wherein n is 2.

In yet another embodiment of the present invention, there are provided a class of substituted piperidine compounds of Formula (I) above wherein n is 3.

Representative substituted azetidine compounds of the invention include, but are not limited to:

5-methyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine;

5-phenyl-3-(2-(S)-azetidinylmethoxy)pyridine;

5-phenyl-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(1-hexynyl)-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)vinyl)-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethyl)-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)vinyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(1-octynyl)-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(1-octynyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(3-aminophenyl)-3-(2-(S)-azetidinylmethoxy)pyridine;

5-bromo-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-phenyl-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(3-thienyl)-3-(1-methyl-2-(R)-azetdinylmethoxy)pyridine;

5-((N-benzoylamino)methyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(benzamidomethyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(acetamidomethyl)-6-chloro-3-(2-(R)-azetidinylmethoxy)pyridine;

5-(6-chlorohexanamidomethyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(3-phenylpropionamidomethyl)-6-chloro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine;

5-(6-chlorobenzamidomethyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-benzoyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-hexanoyl-6-chloro-3-(2-(R)-azetidinylmethoxy)pyridine;

5-(3-quinolinoyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(3-nicotinoyl)-6-chloro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine;

5-(5-pyridinecarbonyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine;

5-(5-carboxy-3-pyridinyl)-3-(2-(R)-azetidinylmethoxy)pyridine;

5-(5-formyl-3-pyridinyl)-3-(2-(S)-azetidinylmethoxy)pyridine;

5-(2-hydroxy-1-naphthyl)-3-(2-(R)-azetidinylmethoxy)pyridine; and

5-(4'-nitro-4-biphenyl)-3-(2-(S)-azetidinylmethoxy)pyridine.

Representative substituted pyrrolidine compounds of the present invention include, but are not limited to:

5-(3-nitrophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(1-naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-methoxyphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-hexynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-furanyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-thienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-pyridyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-vinyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(1-decynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-acetyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-hexyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(5-cyano-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(methoxycarbonyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(5-phenyl-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-trans-(2-phenylethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(1-pyrrolidinylcarbonyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-chlorophenyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-phenylethyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-oxo-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinium;

5-(5-pyrimidinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-phenyl-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-methoxycarbonyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(6-hydroxy-1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride;

5-(5,5-dimethyl-1,3-hexadienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-acetyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethylenyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-pyridinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-quinolinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(1-methyl-2-indolyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3,5-bis(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-chlorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2,4-dichlorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-phenylethynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-methylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-chloro-4-fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-aminophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-formylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-methylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3,3-dimethylbutynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-methylphenyl)ethynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(1-octynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethylenyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-phenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-phenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-phenyl-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-phenyl-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5,6-diphenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5,6-diphenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-bromo-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-bromo-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(3-aminophenyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(4-chlorophenyl)-6-chloro-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(1-octynyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(1-octynyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-phenyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-thienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)vinyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-pyridinyl)ethyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(3-aminophenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-phenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(formamidomethyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-((N-methoxycarbonylamino)methyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(3-nitrobenzamidomethyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-((N-2-pyrrolycarbonylamino)methyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-bromo-6-fluoro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-naphthoyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(4-methyl-1-naphthoyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; methoxy)pyridine;

5-(3-pyridazinecarbonyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2-thiophenecarbonyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(5-carbomethoxypyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(5-bromopyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(6-amino-5-bromopyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(5-bromo-6-methylaminopyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(5-hydroxymethyl-3-pyridinyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(2,4-dimethoxy-5-pyrimidinyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-methyl-3-thienyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine;

5-(4-hydroxymethyl-5-carbomethoxy-3-thienyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4-methoxymethoxy-5-carbomethoxy-3-thienyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-methyl-3-phenyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-methoxy-3-phenyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(2-(4-trifluoromethyl-3-phenyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

5-(4'-fluoro-4-biphenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; and

5-(4'-methyl-4-biphenyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; or a

pharmaceutically acceptable salt thereof.

Representative substituted piperidine compounds of the present invention include, but are not limited to:

5-(furamidomethyl)-6-chloro-3-(2-(R)-piperidinylmethoxy)pyridine;

5-(nicotinamidomethyl)-6-chloro-3-(2-(S)-piperidinylmethoxy)pyridine;

5-(5-nitro-2-furamidomethyl)-6-chloro-3-(1-methyl-2-(R)-piperidinylmethoxy)pyridine;

5-((N-2-pyrazincarbonylamino)methyl)-6-chloro-3-(1-methyl-2-(S)-piperidinylmethoxy)pyridine;

5-(2-phenylacetyl)-6-chloro-3-(1-methyl-2-(R)-piperidinylmethoxy)pyridine;

5-(3-(4-methoxyphenyl)propionyl)-6-chloro-3-(1-methyl-2-(S)-piperidinylmethoxy)pyridine;

5-(2-chloro-3-thienyl)-3-(2-(R)-piperidinylmethoxy)pyridine; and

5-(2-cyano-3-thienyl)-3-(2-(S)-piperidinylmethoxy)pyridine; or a

pharmaceutically acceptable salt thereof.

DEFINITIONS

The term "C₁ -C₆ -alkyl" as used herein refers to a univalent radical derived by removal of a single hydrogen atom from a saturated, straight- or branched-chain hydrocarbon containing between one and six carbon atoms. Examples of C₁ -C₆ -alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, and the like.

The term "haloalkyl" refers to an alkyl group, as defined above, substituted by one or more halogen atoms and includes, for example, trifluoromethyl, chloroethyl, bromobutyl, and the like.

The term "C₁ -C₆ -alkoxy" as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C₁ -C₆ -alkoxy, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.

One or more asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate,malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compounds of Formula (I), as for example, by hydrolysis in blood. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups may be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, edited by E. B. Roche, Pergamon Press (1987).

The term "prodrug ester group" refers to any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to the methods of treatment of the present invention, disorders in synaptic transmission are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat disorders in synaptic transmission, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.001 to 50 mg/kg body weight or more usually from 0.01 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.

ABBREVIATIONS

Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: BOC for t-butyloxycarbonyl; Et₂ O for diethyl ether; EtOAc for ethyl acetate; DEAD for diethylazodticarboxylate; DMF for dimethyl formamide; DPPA for diphenylphosphoryl azide; EDC for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl; EtOAc for ethyl acetate; MeOH for methanol; NaN(TMS)₂ for sodium bis(trimethylsilyl)amide; NMMO for N-methylmorpholine N-oxide; (Ph)₃ for triphenyl; TEA for triethylamine; THF for tetrahydrofuran; TPP for triphenylphosphine.

SYNTHETIC METHODS

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The groups n, R¹, R², R³ and R⁴ are as defined above unless otherwise noted. ##STR6##

In accordance with Scheme 1 intermediate compounds are prepared by reaction of an alcohol compound (1), wherein n is 1 to 3 and R¹ is allyl or C₁ -C₆ -alkyl or a protecting group such as t-BOC or CBZ, for example, with a 3-hydroxypyridine compound (2), wherein R² is H, F or Cl, for compounds of Formula (I) above, in the presence of triphenylphosphine and DEAD under Mitsunobu reaction conditions (cf., Synthesis, 1981: 1) to form the 5-bromopyridyl ether compound (3). ##STR7##

Alternately, in accordance with Scheme 2 selected intermediate pyrrolidine compounds (3), wherein R¹ is allyl or C₁ -C₆ -alkyl or a protecting group such as t-BOC or CBZ, for example, may be prepared by reaction of an pyrrolidinemethanol compound (1) with a 3,5-dibromopyridine compound (4), wherein R² is H or phenyl, in the presence of a strong base, such as an alkyl lithium compound, an alkali metal such as Na or Li, or an alkali metal hydride, such as NaH or KH, for example, in an aprotic solvent such as THF, DMSO or DMF under anydrous conditions and inert atmospheres, at temperatures from room temperature to 120° C., for example. ##STR8##

In accordance with Scheme 3 an intermediate compound (3), wherein R¹ is allyl or C₁ -C₆ -alkyl or a protecting group such as t-BOC or CBZ, for example, is reacted with an unsaturated compound (5), (7) or (9), to give compounds (6), (8) or (10), respectively, which are specific or protected compounds of Formula (I), by treatment with a palladium (II) catalyst under weakly basic conditions at reflux temperature in an organic or aqueous solvent. Compound (5) may be prepared by reacting a compound R³ --CHO, wherein R³ is as described above, with (phenyl)₃ P═CH₂ in refluxing toluene. Compound (7) may be prepared by reacting a compound R³ --CHO, wherein R³ is as described above, with (Ph)₃ P═CH--CHO in refluxing toluene to give R³ --CH═CH--CHO, then reacting R³ --CH═CH--CHO with (Ph)₃ P═CH₂ in refluxing toluene. Compound (9) may be prepared by reacting R³ --CHO, wherein R³ is as described above, with CBr₄ and P(Ph)₃ to give R³ --CH═CBr₂, then reacting R³ --CH═CBr₂ with 2 equivalents of n-butyllithium followed by treatment with H⁺. In the cases wherein R¹ is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I). In some cases wherein R¹ is allyl or C₁ -C₆ -alkyl, it may be desirable to place this grouping in the compound after the protecting R¹ group has been removed. When R¹ is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine. When R¹ is C₁ -C₆ -alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH₃, for example. ##STR9##

In accordance with Scheme 4 an intermediate compound (3), wherein R¹ is allyl or C₁ -C₆ -alkyl or a protecting group such as t-BOC or CBZ, for example, is reacted with a suitable boronic acid compound (11) wherein R³ is as described in options (a)-(l) for Formula (I) above, in the presence of Pd(0) under the conditions of the Suzuki reaction, for example in the presence of a weak base such as NaHCO₃ and in an aprotic solvent, such as toluene, benzene or methylene chloride at reflux temperatures to give a compound (12), wherein R³ is as described above, to produce specific compounds of Formula (I). In an alternate method, compound (11) may be replaced by a R³ MgX compound and reacted in the presence of Ni(dppp)₂ Cl₂ to give compound (12). In the cases wherein R¹ is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I). In some cases wherein R¹ is allyl or C₁ -C₆ -alkyl, it may be desirable to place this grouping in the compound after the protecting R¹ group has been removed. When R¹ is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine. When R¹ is C₁ -C₆ -alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH₃, for example. ##STR10##

In accordance with Scheme 5 are prepared compounds of Formula (I) wherein R² is vinyl, phenyl or substituted phenyl. Reaction of a starting material compound (12) wherein R² is chloro with phenylboronic acid (13) in the presence of Pd(0) under the conditions of the Suzuki reaction, for example in the presence of a weak base such as NaHCO₃ and in an aprotic solvent, such as toluene, benzene or methylene chloride at reflux temperatures to give the compound 14. Reaction of a starting material compound (12) wherein R² is chloro with vinyl-Sn(n-butyl)₃ (15) in the presence of Pd(0) under Stile reaction conditions to give the compound (16). In the cases wherein R¹ is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I). In some cases wherein R¹ is allyl or C₁ -C₆ -alkyl, it may be desirable to place this grouping in the compound after the protecting R¹ group has been removed. When R¹ is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine. When R¹ is C₁ -C₆ -alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH₃, for example. ##STR11##

In Scheme 6 is shown an alternate process for preparing desired compounds of the invention. Whereas in Schemes 1 and 3, the heterocyclic and the pyridine moieties are first joined, and the R³ grouping is added according to Schemes 4 and 5, Scheme 6 allows for the placement of the R³ group before joining. Accordingly compound (2) is treated with the appropriate reagent, such as a trialkylsilyl or benzyl chloride, to protect the hydroxyl group with a protecting group PG, such as trialkylsilyl or benzyl, respectively, for example to give compound (17). Compound (17) may then be reacted with an appropriate reagent, as described in Schemes 4 and 5, to give the compound (18) having the desired substitution at R² and R³. Subsequent deprotection of (18) by standard methods gives (19), which is then coupled with compound (1) according to the method of Scheme 1 to give the desired compound of Formula (I). ##STR12##

In accordance with Scheme 7 are prepared additional compounds of Formula (I). Compund (3) is first reacted with Zn(CN)₂ and tetrakis(triphenylphosphine)palladium(0) under anhydrous conditons in DMF or a similar solvent at room temperature to 120° C. for 12-24 hours, to give the cyano intermediate compound (20). Compound (20) may then be reacted with a reagent R⁵ --M, wherein R⁵ is as described for Formula (I) above and M is lithium or a magnesium halide moiety, under the appropriate anhydrous conditions, with cooling if necessary, for 2-8 hours or until the reaction is complete to give, followed by treatment with aqueous acid to dissociate the metal complexes and give compound (21). Alternately, the cyano group of compound (20) may be reduced by treatment with 1 atm of H₂ in the presence of Raney nickel at room temperature for 1-8 hours to give an intermediate amino compound. The intermediate amino compound may then be treated with a suitable acylating reagent, for example ethyl formate, an acyl chloride R⁶ --Cl, wherein R⁶ is, for example, C₁ -C₈ -alkyl, substituted-C₁ -C₈ -alkyl, phenyl, substituted-phenyl, heteroaryl, substituted-heteroaryl, aryl-C₁ -C₆ -alkyl-, substituted-aryl-C₁ -C₆ -alkyl-, heteroaryl-C₁ -C₆ -alkyl-, or substituted-heteroaryl-C₁ -C₆ -alkyl-, a C₁ -C₆ -alkyl dicarbonate, or an appropriate carbamylating reagent, Cl--CO--N--R⁷ R⁸, for example, wherein R⁷ may be H or C₁ -C₃ -alkyl-, and R⁸ may be H, C₁ -C₃ -alkyl-, phenyl or substituted-phenyl.

In Vitro Determination of Neuronal Nicotinic Receptor Binding Potencies Selectivity and Functionality

For the purpose of identifying compounds as cholinergic agents which are capable of interacting with cholinergic channel receptors in the brain, a ligand-receptor binding assay was carried out as the initial screen. Compounds of the present invention were effective at interacting with neuronal nicotinic cholinergic receptors as assayed in vitro for their ability to displace radioligand from neuronal nicotinic cholinergic channel receptors labeled with [³ H]-cytisine ([³ H]-CYT) (Protocol A below).

For the purpose of directly evaluating the ability of test compounds to functionally activate or inhibit certain subtypes of neuronal nicotinic cholinergic channels, an assay to determine ⁸⁶ Rb⁺ Efflux in IMR-32 cells was employed (Protocol B below).

A. Protocol For Determination of Nicotinic Cholinergic Channel Receptor Binding Potencies of Ligands

Binding of [³ H]-cytisine ([³ H]-CYT) to nicotinic receptors was accomplished using crude synaptic membrane preparations from whole rat brain (Pabreza et al., Molecular Pharmacol., 1990, 39:9). Washed membranes were stored at -80° C. prior to use. Frozen aliquots were slowly thawed and resuspended in 20 volumes of buffer (containing: 120 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 2 mM CaCl₂ and 50 mM Tris-Cl, pH 7.4 @4° C.). After centrifuging at 20,000×g for 15 minutes, the pellets were resuspended in 30 volumes of buffer. Homogenate (containing 125-150 μg protein) was added to triplicate tubes containing concentrations of test compound and [³ H]-CYT (1.25 nM) in a final volume of 500 μL. Samples were incubated for 60 minutes at 4° C., then rapidly filtered through Whatman GF/B filters presoaked in 0.5% polyethyleneimine using 3×4 mL of ice-cold buffer. The filters are counted in 4 mL of Ecolume® (ICN). Nonspecific binding was determined in the presence of 10 μM (-)-nicotine and values were expressed as a percentage of total binding. IC₅₀ values were determined with the RS-1 (BBN) nonlinear least squares curve-fitting program and IC₅₀ values were converted to Ki values using the Cheng and Prusoff correction (Ki=IC₅₀ /(1+[ligand]/Kd of ligand). Alternately, data were expressed as a percentage of the total specific binding. The binding data (shown in Table 1) suggest that the compounds of the present invention have high affinity for the neuronal nicotinic cholinergic channel receptor.

B. Protocols for the Determination of Functional Effects of Cholinergic Channel Receptor Ligands on Synaptic Transmission

Cells of the IMR-32 human neuroblastoma clonal cell line (ATCC, Rockville, Md.) were maintained in a log phase of growth according to established procedures (Lukas, 1993). Experimental cells were seeded at a density of 500,000 cells/ml into a 24-well tissue culture dish. Plated cells were allowed to proliferate for at least 48 hours before loading with 2 μCi/ml of ⁸⁶ Rb⁺ (35 Ci/mmol) overnight at 37° C. The ⁸⁶ Rb⁺ efflux assays were performed according to previously published protocols (Lukas, R. J., J. Pharmacol. Exp. Ther., 265: 294-302, 1993) except serum-free Dulbecco's Modified Eagle's Medium was used during the ⁸⁶ Rb⁺ loading, rinsing, and agonist-induced efflux steps.

EC₅₀ data and maximal responses (reported as percent relative to the response elicited by 100 μM (S)-nicotine) are shown for selected compounds of the invention. The inhibition data (given for a larger number of compounds) reflect inhibition of the efflux elicited by 100 μM (S)-nicotine for either a single dose (% inhibition at 1 μM or at 10 μM) or over a range of doses (IC₅₀ of inhibition). The results (also shown in Table 1) suggest that selected compounds of the present invention either activate or inhibit the initial ion flux aspects of synaptic transmission mediated by neuronal nicotinic acetylcholine receptors. This finding is in agreement with the results of others who have linked dopamine release, which is dependent upon the ion flux in synaptic transmission, to binding at nicotinic receptors (cf., for example, Lippiello and Caldwell, U.S. Pat. No. 5,242,935, issued Sep. 7, 1993; Caldwell and Lippiello, U.S. Pat. No. 5,248,690, issued Sep. 28, 1993; and Wonnacott et al., Prog. Brain Res., 79: 157-163 (1989)).

                  TABLE 1                                                          ______________________________________                                         Binding to Neuronal Nicotinic Receptors                                        Activation or Inhibition of Neuronal Nicotinic Cholinergic                     Channels in Imr-32 Cells                                                                                    % Inhi-                                                                               % Inhi-                                                                               Inhi-                                    Bind-   IMR-72   IMR-32 biton  bition bition                              Ex.  ing     EC.sub.50                                                                               maximal                                                                               @      @      IC.sub.50                           No   (nM)    (μM)  response                                                                              1 μM                                                                               10 μM                                                                              (μM)                             ______________________________________                                          1   0.46                    13                                                 2   4.2                     47                                                 3   0.32                    39                                                 4   0.25                    55                                                 5   0.19                    27                                                 6   0.31                    28                                                 7   0.27                                  46                                   8   0.48                                  10                                   9   36                                    25                                  10   1.2                     32                                                11   0.11                    38                                                12   0.32                    25                                                13   0.12                    50                                                14   0.16                    50                                                15   0.46                    16      83                                        16   0.55                     6                                                17   0.65                    32     100                                        18   0.24                    43                                                19   20                      14                                                20   0.12                                                                      21   0.22                    22                                                22   1.0                     44                                                23   0.065                   27                                                24   0.43                    17                                                25   0.46             4.5                                                      26   0.044                   47                                                27   1.5                     26                                                28   0.16                    20                                                29   0.064                   32                                                30   1.6                     21      90                                        31   0.33                    37                                                32   0.15                                                                      33   0.039   2        47                                                       34   0.021   0.6      88                                                       35   0.39                    34                                                36   0.32                    28                                                37   2.4                     41                                                38   0.082                   29     100                                        39   0.16                    52                                                40   0.16                    30     100                                        41   0.13                    41     100                                        42   0.055                   38                                                43   0.43                    36                                                44   0.56                    30      97                                        45   1.1                     41     100                                        46   0.15                    37                                                47   1.3                     66                                                48   0.34                    40                                                49   0.88                                                                      50   0.0044                                 2                                  51   0.42                    42                                                52   0.39                    22      88                                        53   12                      @5     100                                        55   4.6     >10,000  24.5                                                     56   0.055   3        20     16                                                57   0.79                    21                                                58   0.056   0.8      47                                                       59   0.16                                                                      60   0.22                                                                      61   0.46                                                                      62   0.13                                                                      63   1.6                                                                       64   5.6                                                                       65   0.34                                                                      67   0.024   0.13     90                                                       68   0.11                                                                      69   5.01    >10,000  6                                                        70   0.023                                                                     71   1.9                                                                       72   90.3                                                                      75   0.16                                                                      76   3.2                                                                       77   4.5                                                                       78   92                                                                        79   4.1                                                                       80   23                                                                        81   0.027   1.9      32                                                       82   0.81                                                                      83   0.15                                                                      84   0.0087  0.3      37                                                       85   0.33                                                                      86   0.16    0.25     44                                                       87   0.047   5        40                                                       88   1.8                                                                       89   0.056   0.4      72                                                       90   0.111                                  9                                  91   1.84                                                                      92   0.62    4.9      25                                                       ______________________________________                                    

EXAMPLES

The present invention will be better understood in connection with the following examples, which are intended as an illustration of, and not a limitation upon, the scope of the invention.

Preparations of Starting materials

Several starting materials are used repeatedly throughout the examples that follow. 1-Methyl-2-(S)-pyrrolidinemethanol was obtained from Aldrich Chemical Co. 1-Methyl-2-(R)-pyrrolidinemethanol was obtained from Fluka.

In the PCT Patent Application WO94 08992 of Abreo et al., published Apr. 28, 1994, are disclosed, inter alia, the (R) and (S) 1-BOC-2-(S)-pyrrolidinemethanol compounds and the (R) and (S) 1-BOC-2-(S)-azetidinemethanol compounds

The following procedures were also used to prepare starting materials.

1-BOC-2-(S)-pyrrolidinemethanol

N-BOC-(S)-proline (Sigma Chemical Co., 12.97 g, 60.02 mmol) was dissolved in anhydrous THF and brought to 0° C. with stirring. Borane/THF complex was added dropwise via syringe over a 10 minute period. The reaction mixture was stirred at room temperature for 1 hour, then the reaction was quenched slowly with saturated NaHCO₃ and stirred for an additional hour. The solvent was removed in vacuo, and the residue was diluted with H₂ O. The desired compound was extracted from the aqueous phase with Et₂ O (3×). The organic layer was then washed with brine (2×) dried (MgSO₄) and evaporated.

1-BOC-2-(R)-pyrrolidinemethanol

N-BOC-(R)-proline was converted to the desired product by procedures similar to those for the preparation of the 1-BOC-2-(S)-pyrrolidinemethanol described above.

5-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

a. 5-bromo-3-methoxypyridine

To a suspension of 12 g of 3,5-dibromopyridine and 40 g of 60% NaH in DMF was added 4.05 mL of methanol, and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was taken directly to the next step. MS (DCI/NH₃) m/z 188/190 (M+H)⁺, 205/207 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.32 (d, J=1.8 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.42 (dd, J=1.8, 2.6 Hz, 1H), 3.88 (s, 3H).

b. 5-bromo-3-hydroxypyridine

The compound from the previous step was heated at relux with 60 mL of HBr for 16 hours. The reaction was quenched with excess NaHCO₃, and the basic mixture was extracted with ethyl acetate, and the extract was dried over Na2SO4. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 10% methanol in chloroform. MS (DCI/NH₃) m/z 174/176 (M+H)⁺, 191/193 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.27 (d, J=1.8 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H).

c. 5-bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine

A 332 mg (1.2 mmol) sample of 1-BOC-2-(S)-pyrrolidinemethanol, prepared as described above, and 240 mg (1.38 mmol) of 5-bromo-3-hydroxypyridine, prepared as in step b above, were reacted with triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THF at room temperature for 16 hours, to give 355 mg of the title compound. MS (DCI/NH₃) m/z 357/359 (M+H)⁺, 374/376 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.28 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 4.21-4.05 (m, 2H), 4.03-3.92 (m, 1H), 3.48-3.82 (m, 2H), 2.10-1.80 (m, 4H), 1.47 (s, 9H).

d. 5-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The BOC group was removed from the compound of step c by treatment with TFA in methylene chloride to give the free base of the title compound. The base was converted to the salt by treatment with hydrogen chloride saturated ethanol for 4 hours. The solvents were removed under vacuum to give the title compound. mp 168°-170° C. MS (DCI/NH₃) m/z 257/259 (M+H)⁺, 274/276 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.39 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.90 (dd, J=1.8,2.6 Hz, 1H), 4.50 (dd, J=11, 3.6 Hz, 1H), 4.28 (dd, J=11, 7.7 Hz, 1H), 4.16-4.08 (m, 1H), 3.41 (t, J=7.2 Hz, 2H). Anal. Calc. for C₁₀ H₁₄ N₂ OBrCl•0.9 HCl: C, 36.80; H, 4.60; N, 8.58; Found C, 36.93; H, 4.52; N, 8.58. [α]²⁵ _(D) =+8.65° (c 1.04, MeOH).

5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures described above for the 5-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine, except substituting the 1-BOC-2-(R)-pyrrolidinemethanol for the 1-BOC-2-(R)-pyrrolidinemethanol of step c above, the title compound was prepared. mp MS (DCI/NH₃) m/z 257/259 (M+H)⁺, 274/276 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.28 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 4.21-4.05 (m, 2H), 4.03-3.92 (m, 1H), 3.48-3.82 (m, 2H), 2.10-1.80 (m, 4H), 1.47 (s, 9H).

Anal. Calc. for C₁₀ H₁₄ N₂ OBrCl•0.9 HCl: C, 36.80; H, 4.60; N, 8.58; Found C, 36.93; H, 4.52; N, 8.58.

5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

(S)-1-Methyl-2-pyrrolidinemethanol (4.96 g, 40.0 mmol) was carefully added to a suspension of sodium hydride (1.32 g, 80% yield, 44.0 mmol) in anhydrous DMF (100 mL). After stirring at room temperature for 0.5 hour, 3,5-dibromopyridine (4.83 g, 20.0 mmol) was added, and the reacting mixture was stirred at 50° C. for 4 hours. Another 5.0 mL of water was added, and the solvents were removed under reduced pressure. Again, water (5.0 mL) was added, and the slurry was washed extensively with EtOAc (4×40 mL). The combined organic layers were dried (Na₂ SO₄) and concentrated. The crude product was purified by flash chromatography on silica gel eluting with CHCl₃ /MeOH (10:1) to provide 4.50 g (83% yield) of the title compound. TLC R_(f) 0.33 (10:1 CHCl₃ /MeOH). MS (DCI/NH₃) m/z 271 with ⁷⁹ Br and 273 (M+H)⁺ with ⁸¹ Br. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.37 (d, J=1.8 Hz, 1H, ArH), 8.26 (d, J=2.7 Hz, 1H, ArH), 7.39 (dd, J=1.8, 2.7 Hz, 1H, ArH), 4.01 (dd, J=3.3,11.1 Hz, 1H, OCHH), 3.93 (dd, J=6.9, 11.1 Hz, 1H, OCHH), 3.20-3.10 (m, 1H, NCH), 2.76-2.64 (m, 1H, NCH), 2.49 (s, 3H, NCH₃), 2.40-2.28 (m, 1H, NH), 2.44-2.00 (m, 4H, 2CH₂).

5-bromo-3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridine

(R)-1-methyl-2-pyrrolidinemethanol (430 mg, 13.74 mmol) was dissolved in 14 mL of DMF and stirred under N₂, then 123.4 mg of NaH (80% dispersion in mineral oil) was added. The reaction mixture was stirred fifteen minutes, and 897.4 mg of 3,5-dibromomethylpyridine was added. The reaction mixture was stirred at 50° C. for 16 hours. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel to give 484 mg of the title product. MS (DCI/NH₃) m/z 271/273 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.37 (d, J=1.8, Hz, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.39 (dd, J=1.8, 2.7 Hz, 1H), 4.01 (dd, J=3.3, 11.0 Hz, 1H), 3.93 (dd, J=6.9, 11.1, Hz, 1H), 3.20-3.10 (m, 1H), 3.93 (dd, J=6.9, 11.1 Hz, 1H), 3.20-3.10 (m, 1H), 2.76-2.64 (m, 1H), 2.49 (s, 3H), 2.40-2.28 (m, 1H), 2.44-2.00 (m, 4H).

Example 1 5-(3-Nitrophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

1a. 5-(3-Nitrophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL), were added sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 3-nitrophenylboronic acid (250 mg, 1.50 mmol). The reaction mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (187 mg, 60%). MS (CI/NH₃) m/z 314 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.72-1.97 (m, 3H), 2.03-2.14 (m, 1H), 2.30-2.47 (m, 1H), 2.53 (s, 3H), 2.67-2.80 (m, 1H), 3.12-3.22 (m, 1H), 4.00-4.15 (m, 2H), 7.43-7.46 (m, 1H), 7.63-7.70 (m, 1H), 7.88-7.94 (m, 1H), 8.25-8.31 (m, 1H), 8.38-8.51 (m, 3H).

1b. 5-(3-Nitrophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(3-nitrophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 1a (181 mg, 0.58 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.27 mL, 1.27 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (202 mg, 95%). MS (CI/NH₃) m/z 314 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.07-2.51 (m, 4H), 3.08 (s, 3H), 3.22-3.38 (m, 1H), 3.73-3.86 (m, 1H), 3.91-4.04 (m, 1H), 4.40-4.47 (m, 1H), 4.55-4.64 (m, 1H), 7.72-7.81 (m, 2H), 8.06-8.11 (m, 1H), 8.39 (m, 2H), 8.49-8.57 (m, 2H). Anal. Calcd for C₁₇ H₁₉ N₃ O₃ : C, 52.86; H, 5.48; N, 10.88. Found: C, 52.94; H, 5.53; N, 10.62. [α]²⁵ _(D) =-3.4° (c 1.00, MeOH).

Example 2 5-(1-Naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

2a. 5-(1-Naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL) were added aqueous sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 1-naphthaleneboronic acid (189 mg, 1.10 mmol). The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (196 mg, 62%). MS (CI/NH₃) m/z 319 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.71-1.92 (m, 3H), 2.00-2.10 (m, 1H), 2.27-2.38 (m, 1H), 2.51 (s, 3H), 2.66-2.75 (m, 1H), 3.09-3.17 (m, 1H), 3.98-4.14 (m, 2H), 7.34-7.57 (m, 5H), 7.72-7.96 (m, 3H), 8.36-8.43 (m, 1H).

2b. 5-(1-Naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(1-naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 2a (190 mg, 0.60 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.32 mL, 1.32 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (183 mg, 78%). MS (CI/NH₃) m/z 319 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.04-2.46 (m, 4H), 3.06 (s, 3H), 3.21-3.36 (m, 1H), 3.72-3.84 (m, 1H), 3.88-4.00 (m, 1H), 4.36-4.44 (m, 1H), 4.51-4.57 (m, 1H), 7.51-7.71 (m, 5H), 7.83-7.87 (m, 1H), 8.05-8.11 (, 2H), 8.33-8.43 (m, 2H). Anal. Calcd for C₂₁ H₂₂ N₂ O•2.6 HCl: C, 61.04; H, 6.00; N, 6.78. Found: C, 60.94; H, 5.86; N, 7.03. [α]²⁵ _(D) =-3.2° (c 1.08, MeOH).

Example 3 5-(4-Methoxyphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

3a. 5-(4-Methoxyphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To s solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL) were added sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 4-methoxyphenylboronic acid (228 mg, 1.30 mmol). The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO₄, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (174 mg, 58%). MS (CI/NH₃) m/z 299 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.71-1.92 (m, 3H), 1.99-2.10 (m, 1H), 2.51 (s, 3H), 2.65-2.74 (m, 1H), 3.09-3.17 (m, 1H), 3.87 (s, 3H), 3.96-4.11 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.36 (t, J=3.0 Hz, J=2.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H).

3b. 5-(4-Methoxyphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To s solution of 5-(4-methoxyphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine from step 3a (165 mg, 0.55 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.22 mL, 1.22 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (154 mg, 75%). MS (CI/NH₃) m/z 299 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.05-2.48 (m, 4H), 3.06 (s, 3H), 3.21-3.34 (m, 1H), 3.72-3.85 (m, 1H), 3.91 (s, 3H), 3.88-4.01 (m, 1H), 4.36-4.43 (m, 1H), 4.50-4.58 (m, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 8.24 (s, 1H), 8.45 (s, 1H). Anal. Calcd for C₁₈ H₂₂ N₂ O₂ •2.2 HCl•0.8 H₂ O: C, 55.01; H, 6.62; N, 7.13. Found: C, 54.91; H, 6.62:; N, 7.05. [α]²⁵ _(D) =-3.1° (c 1.09, MeOH).

Example 4 5-Hexynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

4a. 5-Hexynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride (18 mg, 0.025 mmol) and copper (I) iodide (2 mg, 0.025 mmol) in NEt₃ (6.0 mL) was added 1-hexyne (0.237 mL, 2.00 mmol). The mixture was refluxed overnight and cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (174 mg, 64%). MS (CI/NH₃) m/z 273 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.96 (t, J=7.0 Hz, 3H), 1.42-2.10 (m, 8H), 2.26-2.37 (m, 1H), 2.43 (t, J=7.0 Hz, 2H), 2.48 (s, 3H), 2.63-2.71 (m, 1H), 3.08-3.16 (m, 1H), 3.88-4.03 (m, 2H), 4.47-4.55 (m, 1H), 7.17-7.21 (m, 1H), 8.19-8.23 (m, 2H).

4b. 5-Hexynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-hexynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine from step 4a (70 mg, 0.26 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.56 mL, 0.56 mmol). The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (69 mg, 75%). MS (CI/NH₃) m/z 273 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.93 (t, J=7.0 Hz, 3H), 1.43-1.68 (m, 4H), 2.02-2.31 (m, 3H), 2.34-2.47 (m, 1H), 2.48 (t, J=7.0 Hz, 2H), 3.03 (s, 3H), 3.20-3.33 (m, 1H), 3.70-3.84 (m, 1H), 3.86-4.00 (m, 1H), 4.30-4.38 (m, 1H), 4.47-4.55 (m, 1H), 7.48-7.53 (m, 1H), 8.22-8.28 (m, 2H). Anal. Calcd for C₁₇ H₂₄ N₂ O•2.1 HCl•0.2 H₂ O: C, 57.92; H, 7.58; N, 7.97. Found: C, 57.81; H, 7.59; N, 8.11. [α]²⁵ _(D) =-1.7° (c 0.35, MeOH).

Example 5 5-(2-Furanyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

5a. 5-(2-Furanyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of furan (1.45 mL, 20.0 mmol) in THF (30.0 mL) was added sec-butyllithium (1.3M, 7.69 mL, 10.0 mmol) at -78° C. After half an hour at this temperature, trimethyl borate (2.27 mL, 20.0 mmol) was added. The reaction mixture was stirred at -78° C. for one hour and slowly warmed up to room temperature. Solvent was removed, and benzene (10.0 mL), sodium carbonate (2.0M, 5.0 mL), tetrakis(triphenylphosphine)palladium(0) (175 mg) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (1.36 g, 5.0 mmol) were added. The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (1.27 g, 99%). MS (CI/NH₃) m/z 259 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.70-2.22 (m, 4H), 2.28-2.40 (m, 1H), 2.51 (s, 3H), 2.66-2.75 (m, 1H), 3.10-3.18 (m, 1H), 3.97-4.11 (m, 2H), 6.51 (dd, J=4.8 Hz, J=3.6 Hz, 1H), 6.74 (d, J=4.9 Hz, 1H), 7.47 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H).

5b. 5-(2-Furanyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-furanyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 5a (240 mg, 0.93 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 2.14 mL, 2.14 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (278 mg, 90%). mp. 189°-191° C. MS (CI/NH₃) m/z 259 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.08-2.23 (m, 3H), 2.35-2.47 (m, 1H), 3.05 (s, 3H), 3.21-3.32 (m, 1H), 3.74-3.86 (m, 1H), 3.90-4.02 (m, 1H), 4.37-4.44 (m, 1H), 4.55-4.63 (m, 1H), 6.64-6.68 (m, 1H), 6.97-7.01 (m, 1H), 7.68-7.71 (m, 1H), 7.77 (s, 1H), 8.21 (s, 1H), 8.58 (s, 1H). Anal. Calcd for C₁₅ H₁₈ N₂ O₂ •2.0 HCl•0.1 H₂ O: C, 54.10; H, 6.11; N, 8.41. Found: C, 54.13; H, 5.92; N, 8.44. [α]²⁵ _(D) =-6.7° (c 1.00, MeOH).

Example 6 5-(2-Thienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

6a. 5-(2-Thienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL), sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 2-thienylboronic acid (166 mg, 1.30 mmol) were added and the reaction mixture was refluxed overnight, and then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (171 mg, 62%). MS (CI/NH₃) m/z 275 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.75-1.97 (m, 3H), 2.02-2.15 (m, 1H), 2.30-2.50 (m, 1H), 2.57 (s, 3H), 2.67-2.86 (m, 1H), 3.13-3.28 (m, 1H), 3.98-4.12 (m, 2H), 7.12 (t, J=7.3 Hz, 1H), 7.37 (d, J=7.3 Hz, 2H), 7.39 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 8.23 (d, J=3.0 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H).

6b. 5-(2-Thienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-thienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 6a (165 mg, 0.60 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.64 mL, 1.64 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (177 mg, 73%). mp. 201°-203° C. MS (CI/NH₃) m/z 275 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.07-2.24 (m, 3H), 2.32-2.46 (m., 1H), 3.07 (s, 3H), 3.18-3.31 (m, 1H), 3.73-3.84 (m, 1H), 3.90-4.01 (m, 1H), 4.5-4.45 (m, 1H), 4.52-4.61 (m, 1H), 7.22-7.25 (m, 1H), 7.55-7.60 (m, 2H), 7.72 (s, 1H), 8.23 (s, 1H), 8.54 (s, 1H). Anal. Calcd for C₁₆ H₁₉ N₃ O•3.0 HCl•0.2 H₂ O: C, 50.26; H, 5.91; N, 10.99. Found: C, 50.33; H, 5.97; N, 10.61. [α]²⁵ _(D) =-6.1° (c 0.75, MeOH).

Example 7 5-(3-Pyridyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

7a. 5-(3-Pyridyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.0 mmol) in toluene (10.0 mL) was added 3-pyridinyltributyltin (442 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (127 mg, 48%). MS (CI/NH₃) m/z 270 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.70-1.93 (m, 3H), 2.00-2.12 (m, 1H), 2.28-2.39 (m, 1H), 2.52 (s, 3H), 2.67-2.76 (m, 1H), 3.11-3.18 (m, 1H), 3.98-4.13 (m, 2tt), 7.38-7.44 (m, 2H), 7.86-7.92 (m, 1H0, 8.37 (d, J=3.0 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.67 (dd, J=6.0 Hz, J=1.8 Hz, 1H), 8.84 (d, J=2.1 Hz, 1H).

7b. 5-(3-Pyridinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(3-pyridinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 7a (125 mg, 0.47 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in E₂ O, 1.64 mL, 1.64 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (130 mg, 73%). mp. 155°-160° C. MS (CI/NH₃) m/z 270 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.08-2.25 (m, 3H), 2.32-2.44 (m, 1H), 3.08 (s, 3H), 3.17-3.28 (m, 1H), 3.71-3.82 (m, 1H), 3.90-4.03 (m, 1H), 4.38-4.47 (m, 1H), 4.55-4.66 (m, 1H), 7.64-7.71 (m, 1H), 7.79 (s, 1H), 8.23-8.26 (m, 1H), 8.38 (s, 1H), 8.53 (s, 1H), 8.58-8.65 (m, 1H), 8.84 (s, 1H). Anal. Calcd for C₁₆ H₁₉ N₃ O•3.0 HCl•0.2 H₂ O: C, 50.26; H, 5.91; N, 10.99. Found: C, 50.33; H, 5.97; N, 10.61. [α]²⁵ _(D) =-6.1° (c 0.75, MeOH).

Example 8 5-Vinyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

8a. 5-Vinyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.0 mmol) in toluene (10.0 mL) was added vinyltributyltin (362 mL, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (165 mg, 76%). MS (CI/NH₃) m/z 219 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.65-1.95 (m, 3H), 1.97-2.11 (m, 1H), 2.25-2.40 (m, 1H), 2.50 (s, 3H), 2.63-2.74 (m, 1H), 3.08-3.18 (m, 1H), 3.92-4.00 (m, 1H), 4.01-4.09 (m, 1H), 5.38 (d, J=11.4 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 6.68 (dd, (d, J=11.4 Hz, J=17.6 Hz, 1H), 7.26 (dd, J=3.0 Hz, 1H), 8.21 (d, J=3.0 Hz, J=2.1 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H).

8b. 5-Vinyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-vinyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 8a (160 mg, 0.73 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.67 mL, 1.67 mmol). The precipitate formed was filtered, washed Et₂ O) and vacuum-dried to afford the hydrochloride salt (213 mg, 100%). mp. 152°-156° C. MS (CI/NH₃) m/z 219 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.02-2.27 (m, 3H), 2.33-2.44 (m, 1H), 3.05 (s, 3H), 3.20-3.32 (m, 1H), 3.72-3.82 (m, 1H), 3.90-4.00 (m, 1H), 4.37-4.44 (m, 1H), 4.54-4.63 (m, 1H), 5.57 (d, J=11.4 Hz, 1H), 6.03 (d, J=17.6 Hz, 1H), 6.82 (dd, (d, J=11.4 Hz, J=17.6 Hz, 1H), 7.78 (s, 1H), 8.27 7.78 (s, 1H), 8.36 7.78 (s, 1H). Anal. Calcd for C₁₃ H₁₈ N₂ O•2.2 HCl: C, 52.31; H, 6.82; N, 9.38. Found: C, 52.35; H, 6.76; N, 9.14. [α]²⁵ _(D) =-7.8° (c 1.00, MeOH).

Example 9 5-(1-Decynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

9a. 5-(1-Decynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (544 mg, 2.00 mmol), bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.038 mmol) and copper (I) iodide (5 mg, 0.038 mmol) in CH₂ Cl₂ (3.0 mL) and NEt₃ (1.0 mL) was added 1-decyne (0.553 mL, 3.00 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (543 mg, 85%). MS (CI/NH₃) m/z 329 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.90 (t, J=6.9 Hz, 3H), 1.23-2.10 (m, 14H), 2.25-2.41 (m, 1H), 2.41 (t, J=7.3 Hz, 2H), 2.50 (s, 3H), 2.60-2.75 (m, 1H), 3.08-3.21 (m, 1H),, 3.89-4.06 (m, 2H), 7.19 (s, 1H), 8.15-8.28 (m, 2H).

9b. 5-(1-Decynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(1-decynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 9a (180 mg, 0.55 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.26 mL, 1.26 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (163 mg, 74%). mp. 102°-105° C. MS (CI/NH₃) m/z 329 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.95 (m, 3H), 1.33-1.70 (m, 10H), 1.92-2.28 (m, 2H), 2.36-2.46 (m, 2H), 3.034 (s, 3H), 3.20-3.33 (m, 1H), 3.70-3.93 (m, 2H), 4.30-4.55 (m, 2H), 7.32 (s, 1H), 8.00-8.20 (m, 2H). Anal. Calcd for C₂₁ H₃₂ N₂ O•2.0 HCl•0.1 H₂ O: C, 62.55; H, 8.55; N, 6.95. Found: C, 62.57; H, 8.67; N, 6.97. [α]²⁵ _(D) =-5.9° (c 1.28, MeOH).

Example 10 5-Acetyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

10a. 5-(1-Ethoxyvinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.0 mmol) in toluene (10.0 mL) was added (1-ethoxyvinyl)tributyltin (366 mL, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (237 mg, 91%). MS (CI/NH₃) m/z 263 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.43 (t, J=7.2 Hz, 3H), 1.71-1.93 (m, 3H), 1.98-2.11 (m, 1H), 2.50 (s, 3H), 2.63-2.73 (m, 1H), 3.08-3.17 (m, 1H), 3.93 (q, J=7.2 Hz, 2H), 3.93-3.99 (m, 1H), 4.02-4.08 (m, 1H), 4.28 (d, J=3.6 Hz, 1H), 4.69 (d, J=3.6 Hz, 1H), 7.43 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 8.26 (d, J=3.0 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H).

10b. 5-Acetyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(1-ethoxyvinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (100 mg, 0.38 mmol) in MeOH (2.0 mL) was added hydrogen chloride (4.0M in 1,4-dioxane, 2.0 mL). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (117 mg, 100%). MS (CI/NH₃) m/z 235 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.04-2.47 (m, 4H), 2.68 (s, 3H), 3.05 (s, 3H), 3.22-3.32 (m, 1H), 3.73-4.01 (m, 2H), 4.37-4.46 (m, 1H), 4.55-4.63 (m, 1H), 7.93 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 8.53 (d, J=3.0 Hz, 1H), 8.8 (d, J=2.1 Hz, 1H). Anal. Calcd for C₁₃ H₂₀ N₂ O₂ •2.1 HCl•0.3 H₂ O: C, 49.37; H, 6.60; N, 8.86. Found: C, 49.46; H, 6.56; N, 8.61. [α]²⁵ _(D) =-7.0° (c 0.70, MeOH).

Example 11 5-(4-Fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

11a. 5-(4-Fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL) were added sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 4-fluorophenylboronic acid (210 mg, 1.50 mmol). The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (233 mg, 81%). MS (CI/NH₃) m/z 287 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.75-2.15 (m, 4H), 2.31-2.48 (m, 1H), 2.57 (s, 3H), 2.70-2.75 (m, 1H), 3.14-3.28 (m, 1H), 3.99-4.25 (m, 2H), 7.13-7.21 (m, 2H), 7.37 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 7.50-7.58 (m, 2H), 8.31 (d, J=3.0 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H).

11 b. 5-(4-Fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(4-fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine from step 11a (230 mg, 0.80 mmol) in THF (5.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.85 mL, 1.85 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (249 mg, 86%). MS (CI/NH₃) m/z 287 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.08-2.28 (m, 3H), 2.32-2.47 (m, 1H), 3.06 (s, 3H), 3.18-3.30 (m, 1H), 3.72-3.84 (m, 1H), 3.90-4.04 (m, 1H), 4.36-4.46 (m, 1H), 4.55-4.65 (m, 1H), 7.26-7.35 (m, 2H), 7.68-7.74 (m, 3H), 8.31 (d, J=3.0 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H). Anal. Calcd for C₁₇ H₁₉ N₂ OF•2.0 HCl: C, 56.83; H, 5.89; N, 7.80. Found: C, 56.63; H, 5.85; N, 7.66. [α]²⁵ _(D) =-5.6° (c 1.40, MeOH).

Example 12 5-Hexenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

12a. 5-Hexenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-(1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (from Example 4a, 100 mg, 0.37 mmol) in MeOH (3.0 mL) was added Lindlar's catalyst (10 mg). The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOHTEtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (98 mg, 98%). MS (CI/NH₃) m/z 277 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.88 (t, J=4.8 Hz, 3H), 1.23-1.37 (m, 6H), 1.53-1.62 (m, 2H), 1.70-2.08 (m, 4H), 2.26-2.36 (m, 1H), 2.48 (s, 3H), 2.56 (t, J=7.7 Hz, 2H), 2.58-2.71 (m, 1H), 3.07-3.14 (m, 1H), 3.88-4.05 (m, 2H), 7.03 (dd, J=3.0 Hz, J=J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.13 (d, J=3.0 Hz, 1H).

12b. 5-Hexenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-hexenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 12a (92 mg, 0.34 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.77 mL, 0.77 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (113 mg, 84%). MS (CI/NH₃) m/z 277 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.85 (t, J=4.8 Hz, 3H), 1.24-1.33 (m, 6H), 1.60-1.70 (m, 2H), 2.03-2.44 (m, 4H), 2.72 (t, J=7.7 Hz, 2H), 3.04 (s, 3H), 3.15-3.30 (m, 1H), 3.72-3.86 (m, 1H), 3.88-4.00 (m, 1H), 4.34-4.43 (m, 1H), 4.52-4.58 (m, 1H), 7.61 (s, 1H), 8.17 (s, 1H), 8.22 (s, 1H).

Anal. Calcd for C₁₇ H₂₈ N₂ O•2.0 HCl•0.7 H₂ O: C, 56.41; H, 8.74; N, 7.74. Found: C, 56.41; H, 8.77; N, 7.76. [α]²⁵ _(D) =-3.6° (c 1.05, MeOH).

Example 13 5-(2-(4-Pyridinyl)vinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine triihydrochloride

13a. 5-(2-(4-Pyridinyl)vinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272.0 mg, 1.0 mmol) in acetonitrile (3.0 mL) and triethylamine (2.5 mL) was added 4-vinylpyridine (0.227.0 mL, 2.0 mmol), palladium acetate (23.0 mg, 0.1 mmol) and tri-o-tolylphosphine (122.0 mg). After being heated in a sealed tube at 100° C. overnight, the reaction mixture was cooled to room temperature. A minimum amount of saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford a light yellowish oil (259 mg, 88%). MS (CI/NH₃) m/z 295 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.70-2.13 (m, 3H), 2.27-2.41 (m, 1H), 2.53 (s, 3H), 2.66-2.70 (m, 1H), 3.12-3.20 (m, 1H), 3.97-4.14 (m, 2H), 7.07 (d, J=16.6 Hz, 1H), 7.27 (d, J=16.6 Hz, 1H), 7.38 (d, J=5.5 Hz, 2H), 7.39 (dd, J=2.1 Hz, J=3.0 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.62 (d, J=5.5 Hz, 2H).

13b. 5-(2-(4-Pyridinyl)vinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride

To a solution of 5-(2-(4-pyridinyl)vinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 13a (125 mg, 0.42 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.97 mL, 0.97 mmol). The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (151 mg, 97%). mp. 187°-190° C. MS (CI/NH₃) m/z 296 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.05-2.50 (m, 4H), 3.08 (s, 3H), 3.21-3.37 (m, 2H), 3.93-4.03 (m, 1H), 4.46-4.56 (m, 1H), 4.63-4.70 (m, 1H), 7.57 (d, J=16.6 Hz, 1H), 7.83 (d, J=16.6 Hz, 1H), 8.12 (dd, J=2.1 Hz, J=3.0 Hz, 1H), 8.18 (d, J=5.5 Hz, 2H), 8.46 (d, J=3.0 Hz, 1H), 8.63 (d, J=2.1 Hz, 1H), 8.72 (d, J=5.5 Hz, 2H).

Anal. Calcd for C₁₈ H₂₁ N₃ O•3.0 HCl•0.2 H₂ O: C, 52.94; H, 6.02; N, 10.29. Found: C, 53.04; H, 6.17; N, 10.07. [α]²⁵ _(D) =-5.2° (c 1.0, MeOH).

Example 14 5-(5-Cyano-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

14a. 5-(5-Cyano-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (816 mg, 3.00 mmol), bis(triphenylphosphine)palladium(II) chloride (42 mg, 0.06 mmol) and copper (I) iodide (10 mg, 0.06 mmol) in CH₂ Cl₂ (6.0 mL) and NEt₃ (2.0 mL) was added 5-cyanohexyne (0.481 mL, 4.5 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (4 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (674 mg, 79%). MS (CI/NH₃) m/z 284 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.66-2.10 (m, 6H), 2.26-2.87 (m, 1H), 2.48 (s, 3H), 2.54-2.71 (m, 6H), 3.08-3.16 (m, 1H), 3.89-4.03 (m, 2H), 7.20 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 8.24 (d, J=3.0 Hz, 1H).

14b. 5-(5-Cyano-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(5-cyano-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 14a (100 mg, 0.35 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.81 mL, 0.81 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (116 mg, 92%). mp. 165°-167° C. MS (CI/NH₃) m/z 284 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.95-2.48 (m, 7H), 2.64-2.73 (m, 4H), 3.05 (s, 3H), 3.11-3.23 (m, 1H), 3.90-4.02 (m, 1H), 4.39-4.47 (m, 1H), 4.56-4.63 (m, 1H), 7.93 (S, 1H), 8.41 (S, 1H), 8.42 (S, 1H). Anal. Calcd for C₁₇ H₂₁ N₃ O•2.0 HCl: C, 57.31; H., 6.51; N, 11.79. Found: C, 57.57; H, 6.36; N, 11.71. [α]²⁵ _(D) =-3.8° (c 0.60, MeOH).

Example 15 5-(2-(Methoxycarbonyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

15a. 5-(2-(Methoxycarbonyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-(methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (100 mg, 0.40 mmol) in MeOH (3.0 mL) was added palladium on charcoal (10%) (10 mg). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (90 mg, 90%). MS (CI/NH₃) m/z 279 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) d 1.55-2.10 (m, 4H), 2.30-2.60 (m, 2H), 2.52 (s, 3H), 2.65 (t, J=6.3 Hz, 2H), 2.94 (t, J=6.3 Hz, 2H), 3.08-3.21 (m, 1H), 3.68 (s, 3H), 3.90-4.10 (m, 2H), 7.07 (dd, J=3.0, 2.1 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H).

15b. 5-(2-(Methoxycarbonyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-(methoxycarbonyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 15a (90 mg, 0.325 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.81 mL, 0.81 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (114 mg, 100%). MS (CI/NH₃) m/z 279 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) d 2.02-2.50 (m, 5H), 2.83 (t, J=6.3 Hz, 2H), 3.04 (s, 3H), 3.10 (t, J=6.3 Hz, 2H), 3.22-3.32 (m, 1H), 3.90-4.02 (m, 1H), 4.41-4.48 (m, 1H), 4.58-4.66 (m, 1H), 4.71 (s, 3H), 7.92 (dd, J=3.0, 2.1 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.37 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₅ H₂₂ N₂ O₃ •2.1 HCl: C, 50.76; H, 6.84; N, 7.89. Found: C, 50.47; H, 6.78; N, 8.01. [α]²⁵ _(D) =+1.0° (c 0.60, MeOH).

Example 16 5-(2-(Methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

16a. 5-(2-(Methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272.0 mg, 1.0 mmol) in acetonitrile (3.0 mL) and triethylamine (2.5 mL) was added methyl acyrate (0.360 mL, 4.0 mmol), palladium acetate (23.0 mg, 0.1 mmol) and tri-o-tolylphosphine (122.0 mg). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. A minimum amount of saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford a light yellowish oil (205 mg, 74%). MS (CI/NH₃) m/z 277 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.54-2.12 (m, 4H), 2.27-2.43 (m, 1H), 2.52 (s, 3H), 2.65-2.76 (m, 1H), 3.09-3.12 (m, 1H), 3.83 (s, 3H), 3.93-4.07 (m, 2H), 6.48 (d, J=16.2 Hz, 1H), 7.33 (dd, J=3.0, 2.1 Hz, 1H), 7.66 (d, J=16.2 Hz, 1H), 8.33 (d, J=3.0 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H).

16b. 5-(2-(Methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-(methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 16a (100 mg, 0.36 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.83 mL, 0.83 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (121 mg, 96%). mp. 128°-130° C. MS (CI/NH₃) m/z 277 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.04-2.30 (m, 4H), 2.36-2.48 (m, 1H), 3.05 (s, 3H), 3.22-3.32 (m, 1H), 3.92-4.02 (m, 1H), 4.46-4.53 (m, 1H), 4.62-4.68 (m, 1H), 4.71 (s, 3H), 6.78 (d, J=16.2 Hz, 1H), 7.75(d, J=16.2 Hz, 1H), 8.16 (dd, J=3.0, 2.1 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.61 (d, J=3.0 Hz, 1H).

Anal. Calcd for C₁₅ H₂₀ N₂ O₃ •2.0 HCl: C, 51.59; H, 6.35; N, 8.02. Found: C, 51.44; H, 6.38; N, 7.96. [α]²⁵ _(D) =-3.2° (c 0.65, MeOH).

Example 17 5-(5-Phenyl-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

17a. 5-(5-Phenylynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (408 mg, 1.50 mmol), bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.029 mmol) and copper (I) iodide (5 mg, 0.029 mmol) in CH₂ Cl₂ (3.0 mL) and NEt₃ (1.0 mL) was added 5-phenyl-1-pentyne (324 mg, 2.25 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (411 mg, 80%). MS (CI/NH₃) m/z 335 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.65-2.10 (m, 6H), 2.26-2.37 (m, 1H), 2.41-2.47 (m, 2H), 2.48 (s, 3H), 2.61-2.73 (m, 1H), 2.76-2.83 (m, 2H), 3.07-3.16 (m, 1H), 3.89-4.03 (m, 2H), 7.17-7.36 (m, 6H), 8.21-8.26 (m, 2H).

17b. 5-(5-Phenylynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(5-phenylynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 17a (130 mg, 0.39 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.90 mL, 0.90 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (150 mg, 94%). MS (CI/NH₃) m/z 335 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.86-2.01 (m, 2H), 2.03-2.15 (m, 2H), 2.16-2.28 (m, 21H), 2.33-2.54 (m, 3H), 2.74-2.83 (m, 2H), 3.03 (s, 3H), 3.20-3.28 (m, 1H), 3.72-2.82 (m, 1H), 3.86-3.98 (m, 1H), 4.32-4.41 (m, 1H), 4.44-4.55 (m, 1H), 7.22-7.43 (m, 5H), 7.57-7.66 (s, 1H), 8.21-8.39 (m, 1H). Anal. Calcd for C₂₂ H₂₆ N₂ O•2.1 HCl•0.3 H₂ O: C, 63.45; H, 6.97; N, 6.56. Found: C, 63.53; H, 6.97; N, 6.56. [α]²⁵ _(D) =-5.0° (c, 1.1, MeOH).

Example 18 5-trans-(2-Phenylvinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

18a. 5-trans-(2-Phenylvinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272.0 mg, 1.0 mmol) in acetonitrile (3.0 mL) and triethylamine (2.5 mL) was added styrene (231.0 uL, 2.0 mmol), palladium acetate (23.0 mg) and tri-o-tolylphosphine (122.0 mg). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford a light yellowish oil (210.0 mg, 71%). MS (CI/NH₃) m/z 295 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.70-1.92 (m, 2H), 1.99-2.12 (m, 1H), 2.28-2.38 (m, 1H), 2.52 (s, 3H), 2.67-2.74 (m, 1H), 3.10-3.18 (m, 1H), 3.96-4.02 (m, 1H), 4.04-4.11 (m, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.16 (d,=16.0 Hz, 1H), 7.27-7.42 (m, 4H), 7.50-7.54 (m, 2H), 8.22 (d, J=1.2 Hz, 1H), 8.33 (d, J=0.9 Hz, 1H).

18b. 5-trans-(2-Phenylvinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-trans-(2-phenylethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 18a (90 mg, 0.34 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.78 mL, 0.78 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (93 mg, 75%). MS (CI/NH₃) m/z 295 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.88-2.46 (m, 4H), 3.04 (s, 3H), 3.20-3.30 (m, 1H), 3.3.71-3.82 (m, 1H), 3.84-3.99 (m, 1H), 4.35-4.44 (m, 1H), 4.52-4.60 (m, 1H), 7.17-7.53 (m, 5H), 7.62-7.68 (m, 2H), 7.82 (s, 1H), 8.23 (s, 1H), 8.40 (s, 1H). Anal. Calcd for C₁₉ H₂₂ N₂ O•2.0 HCl•0.5 H₂ O: C, 60.64; H, 6.70; N, 7.44. Found: C, 60.68; H, 6.78; N, 7.49. [α]²⁵ _(D) =-4.0° (c 0.73, MeOH).

Example 19 5-(1-Pyrrolidinylcarbonyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

19a. 5-(1-Pyrrolidinylcarbonyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To the ester obtained from Example 27 below was added pyrrolidine (6.0 mL), and the resulting mixture was refluxed for 20 hours. The mixture was concentrated and the residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH/NH₃, 1:10:89 to afford a light yellowsh oil (712 mg, 62% for two steps. MS (CI/NH₃) m/z 290 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.65-2.08 (m, 8H), 2.27-2.87 (m, 1H), 2.49 (s, 3H), 2.63-2.71 (m, 1H), 3.08-3.14 (m, 1H), 3.44-3.51 (m, 2H), 3.63-3.70 (m, 2H), 3.94-4.05 (m, 2H), 7.38 (dd, J=2.0, 3.0 Hz, 1H), 37 (d, J=2.0 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).

19b. 5-(1-Pyrrolidinylcarbonyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To the solution of 5-(1-pyrrolidinylcarbonyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (100 mg, 0.35 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.80 mL, 0.80 mmol). The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (128 mg, 100%). MS (CI/NH₃) m/z 290 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.84-2.48 (m, 8H), 3.04 (s, 3H), 3.20-3.30 (m, 1H), 3.42-3.50 (m, 2H), 3.55-3.62 (m, 2H), 3.73-3.81 (m, 1H), 3.90-4.00 (m, 1H), 4.37-4.43 (m, 1H), 4.54-4.60 (m, 1H), 7.68 (dd, J=2.0 Hz, J=3.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.46 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₆ H₂₃ N₃ O₂ •2.0 HCl•0.8 H₂ O: C, 51.10; H, 7.12; N, 11.71. Found: C, 51.06; H, 7.61; N, 10.71. [α]²⁵ _(D) =-1.7° (c 1.2, MeOH).

Example 20 5-(4-chlorophenyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

20a. 5-(4-chlorophenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 0.84 mmol) and 4-chlorophenylboronic acid (263 mg, 1.68 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (25 mg) and Na₂ CO₃ (1 mL of a 2M solution), and the mixture was heated at reflux for 6 hours. The solvent was removed under vacuum, and the residue was chromatographed on a silica gel column, eluting with 1:5 to 1:2 ethyl acetate/hexane to afford the title compound (325 mg, 100% yield). MS (DCI/NH₃) m/z 389 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.47 (s, 9h), 1.90 (m, 2H), 2.05 (br, 1H), 3.40 (br, 2H), 3.92 (br, 1H), 4.19 (br, 2H), 4.25 (br, 1H), 7.44 (m, 2H), 7.52 (m, 3H), 8.31 (m, 1H), 8.42 (s, 1H).

20b. 5-(4-chlorophenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine hydrochloride

A sample of the compound from step 20a (325 mg, 0.84 mmol) was stirred in TFA (3 mL) and methylene chloride (3.0 mL) for 1/2 hour at 0° C. and 1/2 hour at room temperature. Saturated aqueous NaHCO₃ was added, and the mixture was extracted with methylene chloride. The solution was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with methanol/methylene chloride 5:100 to 10:100 containing 0.3% NH₄ OH to give the free base (241 mg, 99% yield). MS (DCI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.82-2.22 (m, 4H), 3.24 (m, 2H), 3.90 (m, 1H), 4.23 (m, 2H), 7.36 (m, 1H), 7.45 (m, 4H), 8.27 (m, 1H), 8.42 (m, 1H). The free base was converted to the salt with HCl in THF to afford the title compound. mp 180°-182° C. MS (DCI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.93-2.03 (m, 1H), 2.05-2.20 (m, 2H), 2.4 (m, 1H), 3.44 (t, J=7.4 Hz, 2H), 4.19 (m, 1H), 4.43 (dd, J=6.4, 10.7 Hz, 2H), 4.64 (dd, J=3.3, 10.7 Hz, 1H), 7.60 (m, 2H), 7.70 (m, 2H), 8.21 (m, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H). Anal. Calcd for C₁₆ H₁₇ N₂ OCl•2.5 HCl•1.0 H₂ O: C, 48.29; H, 5.45; N, 7.04. Found: C, 48.28; H, 5.07; N, 6.87. [α]²⁵ _(D) =+8.02° (c 0.96, MeOH).

Example 21 5-(2-Phenylethyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

21a. 5-(2-Phenylethyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-phenylethenyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (100 mg, 0.40 mmol) in MeOH (3.0 mL) was added palladium on charcoal (10%) (10 mg). The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (95 mg, 95%). MS (CI/NH₃) m/z 297 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.55-2.09 (m, 4H), 2.25-2.36 (m, 1H), 2.48 (s, 3H), 2.59-2.70 (m, 1H), 2.91 (s, 4H), 3.08-3.15 (m, 1H), 3.84-4.00 (m, 4H), 6.96 (s, 1H), 7.13-7.32 (m, 5H), 8.04 (s, 1H), 8.16 (s, 1H).

21b. 5-(2-Phenylethyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-phenylethyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 21a (95 mg, 0.32 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.73 mL, 0.73 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (86 mg, 73%). MS (CI/NH₃) m/z 297 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.80-2.44 (m, 4H), 3.01 (s, 3H), 2.97-3.17 (m, 4H), 3.19-3.29 (m, 1H), 3.70-3.82 (m, 1H), 3.83-3.93 (m, 1H), 4.26-4.34 (m, 1H), 4.43-4.49 (m, 1H), 7.16-7.42 (m, 5H), 7.58 (s, 1H), 8.13 (s, 1H), 8.24 (s, 1H). Anal. Calcd for C₁₉ H₂₄ N₂ O•2.6 HCl•0.3 H₂ O: C, 57.54; H, 7.07; N, 7.06. Found: C, 57.50; H, 6.93; N, 7.11. [α]²⁵ _(D) =-1.1° (c 0.70, MeOH).

Example 22 5-(3-oxo-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinine dihydrochloride

22a. 5-(3-oxo-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (816 mg, 3.0 mmol) in acetonitrile (9.0 mL) and triethylamine (7.5 mL) was added hex-1-en-3-one (882 mg, 9.0 mmol), palladium acetate (69.0 mg, 1.2 mmol) and tri-o-tolylphosphine (366.0 mg). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford a light yellowish oil (669 mg, 77%). MS (CI/NH₃) m/z 289 CM+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.98 (t, J=7.4 Hz, 3H), 1.60-1.90 (m, 6H), 1.99-2.09 (m, 2H), 2.28-2.40 (m, 1H), 2.50 (S, 3H), 2.67 (t, J=7.4 Hz, 1H), 3.10-3.17 (m, 1H), 3.94-4.06 (m, 2H), 6.86 (d, J=16.1 HZ, 1H), 7.36 (dd, J=1.8, 2.9 Hz, 1H), 7.52 (d, J=16.1 Hz, 1H), 8.33 (d, J=2.9 Hz, 1H), 8.8.36 (d, J=1.8 Hz, 1H).

22b. 5-(3-oxo-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinine dihydrochloride

To a solution of 5-(3-oxo-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinine from step 22a (120 mg, 0.42 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.90 mL, 0.90 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (124 mg, 82%). MS (CI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.94 (t, J=7.4 Hz, 3H), 1.67 (p, J=7.4 Hz, 2H), 2.04-2.47 (m, 4H), 2.81 (t, J=7.4 Hz, 2H), 3.07 (s, 3H), 3.20-3.32 (m, 1H), 3.72-3.81 (m, 1H), 3.90-4.02 (m, 1H), 4.42-4.49 (m, 1H), 4.56-4.65 (m, 1H), 7.01 (d, J=16.1 Hz, 1H), 7.70 (d, J=16.1 Hz, 1H), 8.02 (dd, J=1.8, 2.9 Hz, 1H), 8.45 (d, J=2.9 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H). Anal. Calcd for C₁₇ H₂₄ N₂ O₂•2.1 HCl: C, 55.95; H, 7.21; N, 7.68. Found: C, 55.77; H, 7.48; N, 7.68. [α]²⁵ _(D) =-4.3° (c 0.80, MeOH).

Example 23 Intermediate Compound 5-Bromo-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

23a. 5-Bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of diethyl azodicarboxylate (1.89 mL, 12.0 mmol) in THF (30 mL) was added triphenylphosphine (3.15 g, 12.0 mmol) at 0° C., and the reaction mixture was stirred for half an hour. 1-BOC-(S)-pyrrolidinemethanol (2.41 g, 12.0 mmol) and 5-bromo-6-chloropyridine-3-ol (2.09 g, 10.0 mmol; V. Koch and S. Schnatterer, Synthesis 1990, 499-501)) were then added. The reaction mixture was slowly warmed up to room temperature overnight. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with EtOAc/hexane 1:5 and 1:2 to afford an oil (3.80 g, 97%). MS (CI/NH₃) m/z 391/393 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ01.65-2.05 (m, 4H), 3.20-3.35 (m, 2H), 3.95-4.15 (m, 3H), 7.98 (d, J=2.9 Hz, 1H), 8.21 (d, J=2.9 Hz, 1H).

23b. 5-Bromo-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine from step 23a (150 mg, 0.38 mmol) was added hydrogen chloride (4.0M in 1,4-dioxane, 3.0 mL), and the reaction mixture was allowed to stir at room temperature for two days. A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (119 mg, 94%). mp. 264°-268° C. MS (CI/NH₃) m/z 291/293 (M+H)⁺, 308/310 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.90-2.35 (m, 4H), 3.38-3.46 (m, 2H), 4.07-4.17 (m, 1H), 4.23-4.31 (m, 1H), 4.44-4.51 (m, 1H), 7.90 (d, J=2.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H). Anal. Calcd for C₁₀ H₁₂ N₂ OBrCl•1.0 HCl: C, 32.95; H, 3.87; N, 7.69. Found: C, 36.61; H, 3.95; N, 8.42. [α]²⁵ _(D) =+9.2° (c 0.90, MeOH).

Example 24 Intermediate Compound 5-Bromo-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

24a. 5-(Bromo-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine from Example 23a (300 mg, 0.77 mmol) was added formalin (38%, 3.0 mL) and formic acid (88%, 1.5 mL), and the mixture was refluxed for five hours and then cooled to room temperature. Hydrochloric acid (36%, 0.3 mL) was added, and the mixture was extracted with Et₂ O (3×8 mL). The aqueous layer was heated under vacuum to dryness. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford an oil (214 mg, 91%). MS (CI/NH₃) m/z 305/307 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.60-2.11 (m, 4H), 2.27-2.38 (m, 1H), 2.48 (S, 3H), 2.63-2.72 (m, 1H), 3.07-3.15 (m, 1H), 3.89-4.02 (m, 2H), 7.52 (d, J=3.0 Hz, 1H), 8.04 (d, J=3.0 Hz, 1H).

24b. 5-Bromo-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-bromo-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 24a (100 mg, 0.33 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.75 mL, 0.75 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (85 mg, 76%). mp. 189°-191° C. MS (CI/NH₃) m/z 305/307 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.02-2.47 (m, 4H), 3.03 (S, 3H), 3.22-3.34 (m, 1H), 3.67-3.78 (m, 1H), 3.89-3.99 (m, 1H), 4.32-4.40 (m, 1H), 4.48-4.55 (m, 1H), 7.92 (d, J=3.0 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₁ H₁₄ N₂ OBrCl•1.0 HCl: C, 38.63; H, 4.51; N, 8.19. Found: C, 38.67; H, 4.49; N, 8.13. [α]²⁵ _(D) =-3.8° (c 0.50, MeOH).

Example 25 5-(5-Pyrimidinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

25a. 5-tri-n-Butylstanyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (1.36 g, 5.0 mmol) in toluene (10.0 mL) was added bis(tributyltin) (13.79 mL, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford 5-tri-n-butylstanyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine as an oil (1.09 g, 45%). MS (CI/NH₃) m/z 271 (M+2H--C₁₂ H₂₇ Sn)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.83-0.96 (m, 9H), 1.04-1.13 (m, 6H), 1.25-1.41 (m, 6H), 1.48-1.68 (m, 8H), 1.74-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.28-2.40 (m, 1H), 2.51 (s, 2H), 2.64-2.73 (m, 1H), 3.10-3.20 (m, 1H), 3.90-4.08 (m, 2H), 7.24-7.30 (m, 1H), 8.17-8.23 (m, 2H).

25b. 5-(5-Pyrimidinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-tri-n-butylstanyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 25a (241 mg, 0.5 mmol) in toluene (5.0 mL) was added 5-bromopyrimidine (159 mg, 1.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.18 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (64 mg, 47%). MS (CI/NH₃) m/z 271 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.68-2.12 (m, 4H), 2.28-2.40 (m, 1H), 2.51 (S, 3H), 2.67-2.77 (m, 1H), 3.10-3.18 (m, 1H), 4.00-4.13 (m, 2H), 7.39 (dd, J=2.1, 3.0 Hz), 8.43 (d, J=3.0 Hz, 1H), 8.45 (d, J=2.1 Hz, 1H), 8.97 (s, 1H), 9.28 (s, 1H).

5c. 5-(5-Pyrimidinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-(5-pyrimidinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 25b (60 mg, 0.22 mmol) was added hydrogen chloride (1.0M in Et₂ O, 0.51 mL, 0.51 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (76 mg, 100%). mp. 205°-220° C. MS (CI/NH₃) m/z 271 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.06-2.50 (m, 4H), 3.08 (S, 3H), 3.23-3.33 (m, 1H), 3.72-3.83 (m, 1H), 3.93-4.04 (m, 1H), 4.47-4.55 (m, 1H), 4.64-4.73 (m, 1H), 8.12 (dd, J=2.1, 3.0 Hz), 8.54 (d, J=3.0 Hz, 1H), 8.6 (d, J=2.1 Hz, 1H), 9.13 (s, 1H), 9.24 (s, 1H). Anal. Calcd for C₁₅ H₁₈ N₄ O•2.0 HCl•0.4 H₂ O•0.5 MeOH: C, 50.55; H, 6.29; N, 15.21. Found: C, 50.72; H, 5.90; N, 14.97. [α]²⁵ _(D) =-4.0° (c 0.50, MeOH).

Example 26 5-Phenyl-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

26a. 5-Phenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-phenyl-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (110 mg, 0.36 mmol) in benzene (2.0 mL) were added sodium carbonate (2.0M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and phenylboronic acid (53 mg, 0.43 mmol). The reaction mixture was refluxed overnight, and then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (74 mg, 67%). MS (CI/NH₃) m/z 303 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.65-2.10 (m, 4H), 2.27-2.38 (m, 1H), 2.49 (s, 3H), 2.63-2.72 (m, 1H), 3.08-3.16 (m, 1H), 3.93-4.05 (m, 2H), 7.24 (d, J=3.0 HZ, 1H), 7.44-7.48 (m, 5H), 8.09 (d, J=3.0 Hz, 1H).

26b. 5-Phenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-phenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (70 mg, 0.23 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.53 mL, 0.53 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (50 mg, 58%). mp. 180°-183° C. MS (CI/NH₃) m/z 303 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.04-2.48 (m, 4H), 3.3 (s, 3H), 3.2-3.36 (m, 1H), 3.68-3.83 (m, 1H), 3.88-4.03 (m, 1H). 4.33-4.47 (m, 1H), 4.50-4.62 (m, 1H), 7.50-7.70 (m, 6H), 8.17 (s, 1H). Anal. Calcd for C₁₇ H₁₉ N₂ OCl•2 HCl: C, 58.92; H, 5.87; N, 8.08. Found: C, 58.83; H, 5.74; N, 7.96. [α]²⁵ _(D) =-4.2° (c 0.45, MeOH).

Example 27 5-Methoxycarbonyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

27a. 5-Methoxycarbonyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

A reaction mixture of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride (37 mg, 0.05 mmol) and triethylamine (219 mg) in MeOH (20 mL) was heated at 100° C. under CO (1100 psi) for 68 hours. The catalyst was filtered off and washed with EtOAc. The organics were concentrated and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (88 mg, 35%). MS (CI/NH₃) m/z 251 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.70-2.10 (m, 4H), 2.78-2.87 (m, 1H), 2.50 (s, 3H), 2.66-2.73 (m, 1H), 3.08-3.17 (m, 1H), 3.96 (s, 3H), 3.97-4.07 (m, 2H), 7.78 (d, J=3.0 Hz, J=2.1 Hz), 8.49 (d, J=3.0 Hz, 1H), 8.82 (d, J=2.1 Hz, 1H).

27b. 5-Methoxycarbonyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride (50722-94)

To a solution of 5-methoxycarbonyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 27a (70 mg, 0.28 mmol) in EtOAc (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.64 mL, 0.64 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (74 mg, 82%). mp. 165°-167° C. MS (CI/NH₃) m/z 251 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.04-2.47 (m, 4H), 3.05 (s, 3H), 3.21-3.32 (m, 1H), 3.71-3.82 (m, 1H), 3.91-4.01 (m, 1H), 3.97 (s, 3H), 4.37-4.45 (m, 1H), 4.55-4.62 (m, 1H), 8.52 (d, J=3.0 HZ, 1H), 8.80 (d, J=2.1 Hz, 1H). Anal. Calcd for C₁₃ H₁₈ N₂ O₃ Cl•2.0 HCl: C, 48.29; H, 6.25; N, 8.67. Found: C, 48.33; H, 6.10; N, 8.51. [α]²⁵ _(D) =-2.5° (c 0.40, MeOH).

Example 28 5-(6-Hydroxy-1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

28a. 5-(6-Hydroxy-1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.039 mmol), copper (I) iodide (5 mg, 0.039 mmol) and NEt₃ (1.0 mL) in CH₂ Cl₂ (3.0 mL) was added 5-hexyn-1-ol (0.172 mL, 1.5 mmol). The mixture was refluxed overnight and then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (270 mg, 94%). MS (CI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.55-1.90 (m, 8H), 1.97-2.07 (m, 1H), 2.25-2.46 (m, 1H), 2.27 (s, 3H), 2.46-2.53 (m, 1H), 2.60-2.71 (m, 1H), 3.07-3.16 (m, 1H), 3.68-3.74 (m, 2H), 3.88-4.03 (m, 2H), 7.19 (dd, J=3.0, 1.8 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H).

28b. 5-(6-Hydroxy-1-hexynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(6-hydroxy-hex-1-ynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 28a (120 mg, 0.42 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.96 mL, 0.96 mmol). A precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (143 mg, 95%). MS (CI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.63-1.78 (m, 4H), 2.02-2.57 (m, 6H), 3.03 (s, 3H), 3.20-3.31 (m, 1H), 3.62-3.68 (m, 1H), 3.71-3.82 (m, 1H), 3.90-3.99 (m, 1H), 4.37-4.43 (m, 1H), 4.56-4.60 (m, 1H), 7.82 (s, 1H), 8.36 (s, 1H), 8.37 (s, 1H). Anal. Calcd for C₁₇ H₂₄ N₂ O₂ •2.3 HCl•0.7 H₂ O: C, 53.06; H, 7.25; N, 7.28. Found: C, 52.94; H, 7.38; N, 7.96. [α]²⁵ _(D) =-4.0° (c 0.50, MeOH).

Example 29 5-(2-(4-Pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride

29a. 5-(2-(4-Pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (100 mg, 0.34 mmol) in MeOH (3.0 mL) was added palladium(0) on charcoal (10%) (10 mg). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (87 mg, 87%). MS (CI/NH₃) m/z 298 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.65-2.07 (m, 4H), 2.27-2.36 (m, 1H), 2.49 (s, 3H), 2.59-2.61 (m, 1H), 2.93 (s, 3H), 3.08-3.18 (m, 1H), 3.86-4.02 (m, 2H), 6.96 (dd, J=3.0, 0.9 Hz, 1H), 7.08 (d, J=6.7 Hz, 1H), 8.04 (d, J=0.9 Hz, 1H), 8.19 (d, J=3.0 Hz, 1H), 8.50 (d, J=6.7 Hz, 1H).

19b. 5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride

To a solution of 5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 29a (85 mg, 0.29 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.00 mL, 1.00 mmol). A precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (109 mg, 100%). mp. 148°-150° C. MS (CI/NH₃) m/z 301 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.00-2.44 (m, 4H), 3.04 (s, 3H), 3.19-3.42 (m, 4H), 4.37-4.44 (m, 1H), 4.53-4.60 (m, 1H), 7.78 (dd, J=3.0 Hz, J=0.9 Hz, 1H), 7.87 (d, J=6.7 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H), 8.32 (d, J=3.0 Hz, 1H), 8.63 (d, J=6.7 Hz, 1H). Anal. Calcd for C₁₈ H₂₃ N₃ O•3.3 HCl•1.0 H₂ O: C, 49.62; H, 6.55; N, 9.64. Found: C, 49.66; H, 6.52; N, 9.69. [α]²⁵ _(D) =+1.7° (c 0.60, MeOH).

Example 30 5-(5,5-Dimethyl-1,3-hexadienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

30a. 5-(5,5-Dimethyl-1,3-hexadienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 3.0 mmol) in acetonitrile (3.0 mL) and triethylamine (2.5 mL) was added 5,5-dimethyl-1,3-hexadiene (0.50 mL), palladium acetate (23.0 mg, 0.1 mmol) and tri-o-tolylphosphine (122 mg, 0.1 mmol). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford a light yellowish oil (225 mg, 75%). MS (CI/NH₃) m/z 301 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.08 (S, 9H), 1.55-1.77 (m, 3H), 1.98-2.10 (m, 1H), 2.37-2.47 (m, 1H), 2.50 (s, 3H), 2.64-2.73 (m, 1H), 3.07-3.17 (m, 1H), 3.90-4.06 (m, 2H), 5.93 (d, J=15.5 Hz, 1H), 6.16 (dd, J=15.5, 9.9 Hz, 1H), 6.42 (d, J=15.5 Hz, 1H), 6.78 (dd, J=9.9, 15.5 Hz, 1H), 7.21 (dd, J=3.0, 1.5 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 8.19 (d, J=1.5 Hz, 1H).

30b. 5-(5,5-Dimethyl-1,3-hexadienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(5,5-dimethyl-1,3-hexadienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 30a (140 mg, 0.47 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.07 mL, 1.07 mmol). A precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (137 mg, 78%). mp. 148°-150° C. MS (CI/NH₃) m/z 301 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.07 (S, 9H), 2.03-2.47 (m, 4H), 3.05 (s, 3H), 3.22-3.32 (m, 1H), 3.71-3.83 (m, 1H), 3.92-4.01 (m, 1H), 4.43-4.49 (m, 1H), 4.57-4.84 (m, 1H), 6.19 (d, J=15.5 Hz, 1H), 6.34 (dd, J=15.5, 9.9 Hz, 1H), 6.59 (d, J=15.5 Hz, 1H), 7.50 (dd, J=9.9, 15.5 Hz, 1H), 7.93 (dd, J=3.0, 1.5 Hz, 1H), 8.25 (d, J=3.0 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H). Anal. Calcd for C₁₉ H₂₈ N₂ O•2.5 HCl•0.6 H₂ O: C, 56.71; H, 7.94; N, 6.96. Found: C, 56.77; H, 7.96; N, 7.07. [α]²⁵ _(D) =-4.4° (c 0.75, MeOH).

Example 31 5-(2-Naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

31a. 5-(2-Naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 2-bromonaphthalene (427 mg, 2.0 mmol) in THF (10.0 mL) was added sec-butyllithium (1.3M, 1.69 mL, 2.20 mmol) at -78° C. After half an hour at this temperature, trimethyl borate (0.341 mL, 2.20 mmol) was added. The reaction mixture was kept at the same temperature for one hour then slowly warmed up to room temperature. Solvent was removed, benzene (4.0 mL), sodium carbonate (2.0M, 2.0 mL), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272.0 mg, 1.0 mmol) were added. The reaction mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH₄ OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (242 mg, 76%). MS (CI/NH₃) m/z 319 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.75-2.12 (m, 4H), 2.28-2.40 (m, 1H), 2.53 (s, 3H), 2.67-2.77 (m, 1H), 3.11-3.18 (m, 1H), 4.02-4.15 (m, 2H), 7.50-7.56 (m, 3H), 7.68-7.73 (m, 1H), 7.86-7.96 (m, 3H), 8.04 (s, 1H), 8.33 (s, 1H), 8.59 (s, 1H).

31b. 5-(2-Naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 31b (282 mg, 0.77 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 1.91 mL, 1.91 mmol). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (300 mg, 100%). mp. 248°-251° C. MS (CI/NH₃) m/z 319 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.03-2.51 (m, 4H), 3.07 (s, 3H), 3.23-3.36 (m, 1H), 3.74-3.83 (m, 1H), 3.86-3.99 (m, 1H), 4.36-4.45 (m, 1H), 4.50-4.58 (m, 1H), 7.60-7.67 (m, 2H), 7.72-7.78 (m, 1H), 7.93-8.05 (m, 4H), 8.12 (s, 1H), 8.24 (s, 1H), 8.58 (s, 1H).

Anal. Calcd for C₂₁ H₂₂ N₂ O•2.1 HCl: C, 63.86; H, 6.15; N, 7.09. Found: C, 63.85; H, 6.06; N, 7.01. [α]²⁵ _(D) =-5.8° (c 1.1, MeOH).

Example 32 5-Acetyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

32a. 5-(1-Ethoxyvinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (500 mg, 1.28 mmol) in toluene (10.0 mL) was added (1-ethoxyvinyl)tributyltin (489 mL, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.-45 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (568 mg, >100%; some tin reagent contamination). MS (CI/NH₃) m/z 383 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.25-1.45 (m, 3H), 1.47 (s, 9H), 1.55-1.71 (m, 1H), 1.98-2.07 (m, 3H), 3.32-3.45 (m, 1H), 3.87-3.96 (m, 2H), 4.05-4.21 (m, 3H), 4.43-4.47 (m, 2H), 7.26-7.34 (m, 1H), 8.03-8.06 (m, 1H).

32b. 5-Acetyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(1-ethoxyvinyl)-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine from step 32a (165 mg, 0.43 mmol) was added hydrogen chloride (4.0M in 1,4-dioxane, 4.0 mL), and the mixture was stirred at room temperature for two days. The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (92 mg, 73%). mp 173°-176° C. MS (CI/NH₃) m/z 255 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.90-2.36 (m, 4H), 2.71-2.75 (m, 1H), 3.39-3.46 (m, 2H), 4.09-4.20 (m, 1H), 4.25-4.33 (m, 1H), 4.50-5.56 (m, 1H), 4.75-5.86 (m, 2H), 7.76 (d, J=3.0 Hz, 1H), 8.26 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₂ H₁₅ N₂ O₂ Cl•1.2 HCl•0.1 H₂ O: C, 47.97; H, 5.34; N, 9.04. Found: C, 48.00; H, 5.50; N, 9.30. [α]²⁵ _(D) =+12° (c 0.60, MeOH).

Example 33 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

33a. 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(S)pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (500 mg, 1.28 mmol) in acetonitrile (4.0 mL) was added 4-vinylpyridine (156 mg, 1.5 mmol), palladium acetate (29.0 mg, 0.12 mmol), tri-o-tolylphosphine (156 mg, 0.12 mmol) and triethylamine (3.2 mL). The reaction mixture was heated in a sealed tube at 100° C. overnight, then cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with 4 to 50% ether in hexane) to give the title compound (282 mg). MS (CI/NH₃) m/z 416 (M+H)⁺.

33b. 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine from step 33a (100 mg) was added hydrogen chloride (4.0M in 1,4-dioxane, 4.0 mL), and the mixture was stirred at room temperature for two days. The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (92 mg, 73%). mp 235°-240° C. MS (CI/NH₃) m/z 316 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.76-2.22 (m, 4H), 2.25-3.80 (m, 1H), 3.43 (t, J=7.2, 1H), 4.18 (dq, J=3.8, 8.0, 1H), 4.32 (dd, J=7.8, 10.8, 1H), 4.53 (dd, J=3.3, 10.5, 1H), 7.45 (d, J=16.3, 1H), 7.90 (d, J=3.0, 1H), 7.96 (d, J=16.3, 1H), 8.16 (d, J=2.7, 1H), 8.20 (d, J=7.2, 2H), 8.71 (d, J=7.0, 2H). Anal. Calcd for C₁₇ H₁₈ N₃ OCl•2.8 HCl: C, 48.63; H, 5.47; N, 10.01. Found: C, 48.73; H, 5.47; N, 9.86. [α]²⁵ _(D) =+1.78° (c 0.45, MeOH).

Example 34 5-(3-Pyridinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

34a. 5-(3-Pyridinyl)-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (from Example 23a, 500 mg, 1.28 mmol) in toluene (10.0 mL) was added 3-pyridinyltributyltin (564 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (428 mg, 86%). MS (CI/NH₃) m/z 390 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.24-1.67 (m, 2H), 1.44 (s, 9H), 1.86-2.10 (m, 2H), 3.32-3.45 (m, 2H), 3.95-4.27 (m, 3H), 7.28-7.44 (m, 2H), 7.81-7.86 (m, 1H), 8.14-8.17 (m, 1H), 8.65-8.73 (m, 2H).

34b. 5-(3-Pyridinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(3-pyridinyl)-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine from step 34a (170 mg, 0.44 mmol) was added HCl (4.0M in 1,4-dioxane, 3.0 mL), and the mixture was stirred at room temperature for two days. The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (92 mg, 73%). mp 195°-198° C. MS (CI/NH₃) m/z 290 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.90-2.34 (m, 4H), 3.36-3.45 (m, 2H), 4.09-4.20 (m, 1H), 4.26-4.33 (m, 1H), 4.50-4.56 (m, 1H), 7.64-7.67 (m, 1H), 8.04-8.09 (m, 1H), 8.24-8.28 (m, 1H), 8.58-8.64 (m, 1H), 8.80-8.5 (m, 1H), 8.93-8.97 (m, 1H). Anal. Calcd for C₁₅ H₁₆ N₃ OCl•2.0 HCl: C, 49.68; H, 5.00; N, 11.59. Found: C, 49.50; H, 4.99; N, 11.32. [α]²⁵ _(D) =+5.6° (c 1.00, MeOH).

Example 35 5-(3-Quinolinyl)-(3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride

35a. Quinoline-3-boronic acid

3-Bromoquinoline (0.4 mL, 3 mmol) was dissolved in THF, and the solution was cooled to -78° C. To this solution was added t-butyllithium (4.1 mL, 7 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.81 mL, 7.1 mmol) was added at -78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue 180 mg was taken directly to the next step.

35b. 5-(3-Quinolinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of the compound from step 35a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (271 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na₂ CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 4 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2 to 5% methanol in methylene chloride in a first column, followed by rechromatography, eluting with 0.1 to 1% ether in hexane, to afford 120 mg of the title compound. MS (CI/NH₃) m/z 320 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.82, (m, 3H), 2.06 (m, 1H), 2.34 (m, 1H), 2.52 (s, 3H), 2.73 (m, 1H), 3.13 (m, 1H), 4.09 (m, 2H), 7.52 (m, 1H), 7.62, (m, 1H), 7.76 (m, 1H), 7.90 (m, 1H), 8.16 (m, 1H), 8.32 (m, 1H), 8.40 (m, 1H), 8.58 (m, 1H).

35c. 5-(3-Quinolinyl)-3-(1-methyl2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride

To a solution of 5-(3-Quinolinyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine from step 35b (117.2 mg) in THF/ether (1.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.90 mL). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (133 mg). mp 184°-186° C. MS (CI/NH₃) m/z 320 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ9.47 (d, J=2.0 Hz, 1H), 9.36 (d, J=20 Hz, 1H), 8.85 (dd, J=1.7 Hz, 1H), 8.63) d, J=2.7 Hz, 1H), 8.34 (m, 3H), 8.20 (m, 1H), 8.01 (m, 1H), 4.73 (m, 1H), 4.57 (dd, J=5.8, 11.2 Hz 1H), 4.03 (m, 1H), 3.81 (m, 1H), 3.30 (m, 1H), 3.10 (s, 3H), 2.45 (m, 1H), 2.29-2.12 (br, 3H). Anal. Calcd for C₂₀ H₂₁ N₃ O•3.1 HCl•0.3 H₂ O: C, 54.87; H, 5.69; N, 9.59. Found: C, 55.22; H, 5.87; N, 9.14. [α]²⁵ _(D) =-8.15° (c 0.54, MeOH).

Example 36 5-(1-methyl-2-indolyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride

36a. 1-methylindol-2-boronic acid

1-Methylindole (0.38 mL, 3 mmol) was dissolved in THF (10 mL), and the solution was cooled to -78° C. To this solution was added sec-butyllithium (1.9 mL, 2.5 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.34 mL, 3 mmol) was added at -78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue was taken directly to the next step.

36b. 5-(1-methyl-2-indolyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of the compound from step 36a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (270 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na₂ CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 60 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 105 mg of the title compound. MS (CI/NH₃) m/z 322 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.80 (m, 3H), 2.05 (m, 1H), 2.32 (m, 1H), 2.50 (s, 3H), 2.70 (m, 1H), 3.13 (m, 1H), 3.78 (s, 3H), 4.04 (m, 2H), 6.62 (s, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.66 (m, 1H), 8.38 (m, 2H).

36c. 5-(1-methyl-2-indolyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride

To a solution of the compound from step 36b (117.2 mg) in THF/ether was added hydrogen chloride (1.0M in Et₂ O). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt. mp 195°-197° C. MS (CI/NH₃) m/z 322 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.37 (d, J=1.6 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H), 7.58 (m, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.22 (m, 1H), 7.09 (m, 1H), 4.13 (m, 1H), 4.01 (m, 1H), 4.03 (m, 1H), 3.78 (s, 3H), 2.95 (m, 1H), 2.61 (m, 1H), 2.20 (m, 1H), 1.93 (m, 1H), 1.72-1.60 (m, 3H). Anal. Calcd for C₂₀ H₂₃ N₃ O•1.4 HCl: C, 64.49; H, 6.60; N, 11.28. Found: C, 64.37; H, 6.71; N, 10.90. [α]²⁵ _(D) =-12.59° (c 1.00, MeOH).

Example 37 5-(3,5-bis(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

37a. 5-(3,5-bis(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of 3,5-bis(trifluoromethyl)phenylboronic acid (0.55 g, 2.0 mmol, Lancaster Chem Co.) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 1.1 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na₂ CO3 (1 mL of a 2M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 225 mg of the title compound. MS (CI/NH₃) m/z 405 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.8 (m, 3H), 2.08 (m, 1H), 2.36 (m, 1H), 2.54 (s, 3H), 2.78 (m, 1H), 3.17 (m, 1H), 4.10 (m, 2H), 7.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 8.48 (m, 1H).

37b. 5-(3,5-bis(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of the compound from step 37a (225 mg) in THF/ether was added hydrogen chloride (1.0M in Et₂ O). A precipitate formed which was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (195 mg). mp 68°-70° C. MS (CI/NH₃) m/z 405 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.66 (d, J=1.7 Hz, 1H), 8.50 (d, J=2.7, 1H), 8.28 (s, 2H), 8.22 (s, 1H), 8.06 (m, 1H), 4.67 (dd, J=3.8, J=11.9 Hz, 1H), 4.52 (dd, J=6.2, 11.2 Hz, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 3.28 (m, 1H), 3.07 (s, 3H), 2.42 (m, 1H), 2.24 (m, 1H), 2.12 (m, 2H). Anal. Calcd for C₁₈ H₁₉ N₃ OF₆ •2 HCl: C, 47.82; H, 4.22; N, 5.87. Found: C, 47.60; H, 4.53; N, 5.86. [α]²⁵ _(D) =-6.60° (c 0.53, MeOH).

Example 38 5-(4-chlorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 4-chlorophenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), and carrying the product forward as in step 37c, the title compound was prepared (190 mg). mp 224°-226° C. MS (CI/NH₃) m/z 302 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.48 (d, J=1.7 Hz, 1H), 8.32 (d, J=2.7, 1H), 7.75 (t, J=2.4, 1H), 7.65 (m, 2H), 7.56 (m, 2H), 4.58 (dd, J=3.1, 11.2 Hz, 1H), 4.41 (dd, J=5.7, 11.1 Hz, 1H), 3.95 (m, 1H), 3.77 (m, 1H), 3.27 (m, 1H), 3.06 (s, 3H), 2.42 (m, 1H), 2.23 (m, 1H), 2.13 (m, 2H). Anal. Calcd for C₁₇ H₁₉ N₂ OCl•2 HCl•0.1 H₂ O: C, 54.09; H, 5.66; N, 7.42. Found: C, 53.75; H, 5.62; N, 7.07. [α]²⁵ _(D) =-5.07° (c 0.67, MeOH).

Example 39 5-(2,4-dichlorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 2,4-dichlorophenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), and carrying the product forward as in step 37c, the title compound was prepared (96 mg). mp 176°-178° C. MS (CI/NH₃) m/z 337 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.41 (d, J=2.5 Hz, 1H), 8.36 (d, J=1.4, 1H), 7.77 (m, 1H), 7.50 (dd, J=2.2, 8.5, 1H), 7.43 (d, J=8.1, 2H), 4.58 (dd, J=3.3, 11.4, 1H), 4.42 (dd, J=5.9, 11.0, 1H), 3.95 (m, 1H), 3.76 (m, 2H), 3.26 (m, 1H), 3.05 (s, 3H), 2.41 (m, 1H), 2.21 (m, 1H), 2.09 (m, 2H). Anal. Calcd for C₁₇ H₁₈ N₂ OCl₂ •2 HCl•0.6 MeO: C, 49.23; H, 5.26; N, 6.52. Found: C, 49.38; H, 5.47; N, 6.17. [α]²⁵ _(D) =-7.67° (c 0.86, MeOH).

Example 40 5-(2-phenylethynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 1 mmol) in 6 mL of methylene chloride was added triethylamine (0.5 mL), Pd(II) (19 mg), CuI (a catalytic amount) and 0.22 mL of phenylacetylene (2 mmol). The reaction mixture was heated at reflux for 40 hours. The solvent was removed under reduced pressure, and the free base was purified by chromatography, during with 2 to 6% methanol in methylene chloride. MS (CI/NH₃) m/z 293 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.07 (m, 2H), 2.25 (m, 2H), 2.81 (m, 1H), 2.88 (s, 3H), 3.47 (m, 1H), 3.67 (m, 1H), 4.23 (m, 1H), 4.64 (m, 1H), 7.38 (m, 4H), 7.54 (m, 2H), 8.28 (m, 1H), 8.42 (m, 1H). The salt was prepared by treatment with HCl in ether, as described above to give 90 mg of the title compound. mp 190°-192° C. MS (CI/NH₃) m/z 293 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.39 (d, J=1.5, 1H), 8.30 (d, J=2.6, 1H), 7.65 (m, 3H), 7.48 (m, 3H), 4.54 (dd, J=3.3, 11.0, 1H), 4.38 (dd, J=5.9, 11.4, 1H), 3.94 (br, 1H), 3.26 (br, 1H), 3.05 (s, 3H), 2.41 (m, 1H), 21.4 (m, 1H), 2.09 (m, 2H). Anal. Calcd for C₁₉ H₂₀ N₂ O•2.2 HCl: C, 61.25; H, 6.01; N, 7.52. Found: C, 61.14; H, 5.84; N, 7.52. [α]²⁵ _(D) =-10.00° (c 0.22, MeOH).

Example 41 5-(4-methylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 4-methylphenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), then carrying the product forward as in step 37c, the title compound was prepared (100 mg). mp 204°-206° C. MS (CI/NH₃) m/z 283 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.52 (s, 1H), 8.32 (d, J=2.7, 1H), 7.83 (m, 1H), 7.63 (d, J=8.1, 2H), 7.42 (d, J=8.2, 2H), 4.60 (dd, J=4.5, 11.1, 1H), 4.43 (dd, J=6.1, 11.5, 1H), 3.95 (m, 1H), 3.76 (m, 1H), 3.27 (m, 1H), 3.06 (s, 3H), 2.42 (m, 1H), 2.41 (s, 3H), 2.23 (m, 1H), 2.12 (m, 2H). Anal. Calcd for C₁₈ H₂₂ N₂ O•2.5 HCl•0.5 H₂ O: C, 56.52; H, 6.72; N, 7.32. Found: C, 56.22; H, 6.85; N, 6.94. [α]²⁵ _(D) =-5.48° (c 0.42, MeOH).

Example 42 5-(3-chloro-4-fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 3-chloro-4-fluorophenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), then carrying the product forward as in step 37c, the title compound was prepared (120 mg). mp 202°-204° C. MS (CI/NH₃) m/z 321 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.54 (s, 1H), 8.41 (d, J=2.4, 1H), 7.95 (s, 1H), 7.84 (dd, J=2.4, 6.8, 1H), 7.63 (m, 1H), 7.41 (t, J=8.8, 1H), 4.64 (dd, J=3.0, 11.2, 1H), 4.47 (dd, J=6.2, 11.2, 1H), 3.98 (m, 1H), 3.78 (m, 1H), 3.28 (m, 1H), 3.07 (s, 3H), 2.42 (m, 1H), 2.23 (m, 1H), 2.13 (m, 2H). Anal. Calcd for C₁₇ H₁₈ N₂ OClF•2 HCl•0.5 MeO•0.4 H₂ O: C, 50.41; H, 5.51; N, 6.72. Found: C, 50.41; H, 5.43; N, 6.37. [α]²⁵ _(D) =-4.64° (c 0.69, MeOH).

Example 43 5-(3-aminophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 3-aminophenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), then carrying the product forward as in step 37c, the title compound was prepared (250 mg). mp 80°-82° C. MS (CI/NH₃) m/z 283 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.58 (m, 1H), 8.40 (m, 1H), 7.98 (m, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.37 (m, 1H), 7.21 (m, 1H), 4.64 (dd, J=3.1, 11.2, 1H), 4.48 (dd, J=6.1, 11.2, 1H), 3.98 (m, 1H), 3.78 (m, 1H), 3.28 (m, 1H), 3.07 (s, 3H), 2.43 (m, 1H), 2.24-2.08 (m, 3H). Anal. Calcd for C₁₇ H₂₁ N₃ O•2.2 HCl•0.8 H₂ O: C, 54.02; H, 6.61; N, 11.12. Found: C, 53.96; H, 6.62; N, 10.82. [α]²⁵ _(D) =-7.50° (c 1.00, MeOH).

Example 44 5-(2-formylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 2-formylphenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), then carrying the product forward as in step 37c, the title compound was prepared (250 mg). MS (CI/NH₃) m/z 297 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ9.89 (s, 1H), 8.44 (m, 1H), 8.31 (m, 1H), 8.07 (m, 1H), 7.85 (m, 1H), 7.73 (m, 2H), 7.54 (m, 1H), 4.58 (dd, J=3.0, 11.1, 1H), 4.42 (dd, J=5.9, 11.0, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.27 (m, 1H), 3.06 (s, 3H), 2.42 (m, 1H), 2.23 (m, 1H), 2.13 (m, 2H). Anal. Calcd for C₁₈ H₂₀ N₂ O•2 HCl: C, 58.54; H, 6.00; N, 7.59. Found: C, 58.61; H, 6.16; N, 7.62. [α]²⁵ _(D) =-7.06° (c 0.42, MeOH).

Example 45 5-(2-methylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 2-methylphenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), then carrying the product forward as in step 37c, the title compound was prepared (140 mg). MS (CI/NH₃) m/z 283 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ9.89 (s, 1H), 8.57 (s, br, 1H), 8.40 (s, br, 1H), 7.94 (s, br, 1H), 7.37 (m, 2H), 7.31 (m, 2H), 4.63 (dd, J=3.4, 11.2, 1H), 3.97 (m, 1H), 3.29-3.22 (m, 1H), 3.09 (s, 3H), 2.44 (m, 1H), 2.31 (s, 3H), 2.24 (m, 1H), 2.18-2.09 (m, 2H). Anal. Calcd for C₁₈ H₂₂ N₂ O•2 HCl: C, 60.85; H, 6.81; N, 7.88. Found: C, 61.06; H, 6.96; N, 7.85. [α]²⁵ _(D) =-13.80° (c 0.36, MeOH).

Example 46 5-(4-(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 37b, except substituting 4-(trifluoromethyl)phenylboronic acid for the boronic acid reagent thereof and Pd(Ph₃ P)₄ for the Pd(0), then carrying the product forward as in step 37c, the title compound was prepared (200 mg). MS (CI/NH₃) m/z 337 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.52 (d, J=1.5, 1H), 8.35 (d, J=2.6, 1H), 7.84 (s, 4H), 7.78 (m, 1H), 4.59 (dd, J=2.9, 11.0, 1H), 4.42 (dd, J=6.3, 11.4, 1H), 3.96 (m, 1H), 3.78 (m, 1H), 3.28 (m, 1H), 3.07 (s, 3H), 2.43 (m, 1H), 2.25 (m, 1H), 2.14 (m, 2H). Anal. Calcd for C₁₈ H₁₉ N₂ OF₃ •2.2 HCl•0.2 H₂ O: C, 51.45; H, 5.18; N, 6.70. Found: C, 51.41; H, 5.15; N, 6.36. [α]²⁵ _(D) =-4.70° (c 0.60, MeOH).

Example 47 5-(3,3-dimethylbutynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (270 mg, 1 mmol) in 5 mL of methylene chloride was added triethylamine (0.5 mL), Pd(II) (19 mg), CuI (a catalytic amount) and 0.3 mL of 3,3-dimethyl-1-butyne (2 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with methylene chloride, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The free base was purified by chromatography, eluting with 1 to 2% methanol in methylene chloride. MS (CI/NH₃) m/z 273 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.32 (s, 9H), 1.80 (br m, 3H), 2.05 (m, 1H), 2.36 (m, 1H), 2.52 (s, 3H), 2.73 (m, 1H), 3.17 (m, 1H), 3.95 (m, 1H), 4.05 (m, 1H), 7.18 (m, 1H), 8.20 (m, 2H). The salt was prepared by treatment with HCl in ether, as described above, to give 100 mg of the title compound. MS (CI/NH₃) m/z 273 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.44 (d, J=2.2, 1H), 8.40 (s, 1H), 8.01 (m, 1H), 4.61 (dd, J=2.9, 11.1, 1H), 4.54 (dd, J=5.5, 11.0, 1H), 3.96 (m, 1H), 3.26 (m, 1H), 3.05 (s, 3H), 2.41 (m, 1H), 2.22 (m, 1H), 2.10 (m, 2H). Anal. Calcd for C₁₇ H₂₄ N₂ O•2.0 HCl•0.4 H₂ O: C, 57.92; H, 7.66; N, 7.95. Found: C, 58.10; H, 7.74; N, 7.57. [α]²⁵ _(D) =-7.70° (c 1.46, MeOH).

Example 48 5-(2-(4-methylphenyl)ethynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (200 mg, 0.7 mmol) in 5 mL of methylene chloride was added triethylamine (0.4 mL), Pd(II) (12 mg), CuI (a catalytic amount) and 0.15 mL of 2-methyl-5-ethynylpyridine (0.14 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with methylene chloride, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The free base was purified by chromatography, eluting with 1 to 2% methanol in methylene chloride. MS (CI/NH₃) m/z 307 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.50 (m, 3H), 1.79 (m, 3H), 2.04 (m, 1H), 2.30 (m, 1H), 2.50 (s, 3H), 2.67 (m, 1H), 3.12 (m, 1H), 3.98 (m, 2H), 7.18 (m, 2H), 7.32 (m, 1H), 7.43 (m, 2H), 8.26 (m, 1H). The salt was prepared by treatment with HCl in ether, as described above, to give 120 mg of the title compound. mp 197°-199° C. MS (CI/NH₃) m/z 307 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.49 (d, J=1.5, 1H), 8.42 (d, J=2.6, 1H), 7.98 (m, 1H), 7.55 (d, J=8.1 (2H), 7.32 (d, J=7.7, 2H), 4.60 (dd, J=3.0, 11.1, 1H), 4.44 (dd, J=5.9, 11.4, 1H), 3.96 (m, 1H), 3.77 (m, 1H), 3.26 (m, 1H), 3.05 (s, 3H), 2.41 (m, 1H), 2.38 (s, 3H), 2.23 (m, 1H), 2.12 (m, 2H). Anal. Calcd for C₂₂ H₂₄ N₂ O•2.0 HCl•1.1 H₂ O: C, 60.18; H, 6.62; N, 7.02. Found: C, 59.98; H, 6.58; N, 6.77. [α]²⁵ _(D) =-3.70° (c 0.54, MeOH).

Example 49 5-octynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 0.1 mmol) in 6 mL of methylene chloride was added triethylamine (0.4 mL), Pd(II) (18 mg), CuI (a catalytic amount) and 0.3 mL of 1-octyne (0.2 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with methylene chloride, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The free was purified by chromatography, eluting with 1 to 2% methanol in methylene chloride. MS (CI/NH₃) m/z 301 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.91 (μ, 3H), 1.32 (μ, 4H), 1.60 (μ, 2H), 1.90 (μ, 3H), 2.15 (μ, 1H), 2.42 (μ, 2H), 2.64 (σ, 3H), 2.98 (βρ σ, 1H), 3.34 (βρ σ, 1H), 4.04 (μ, 1H), 4.25 (μ, 1H), 7.22 (μ, 1H), 8.22 (μ, 2H). The salt was prepared by treatment with HCl in ether, as described above, to give 110 mg of the title compound. MS (CI/NH₃) m/z 301 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ8.45 (d, J=2.6, 1H), 8.42 (d, J=1.1, 1H), 8.07 (m, 1H), 4.63 (dd, J=3.0, 11.1, 1H), 4.47 (dd, J=5.9, 11.4, 1H), 3.97 (m, 1H), 3.78 (m, 1H), 3.27 (m, 1H), 3.05 (s, 3H), 2.51 (t, J=7.0, 2H), 2.42 (m, 1H), 2.23 (m, 1H), 2.10 (m, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 1.33 (m, 4H), 0.88 (m, 3H). Anal. Calcd for C₁₉ H₂₈ N₂ O•2.0 HCl: C, 61.12; H, 8.10; N, 7.50. Found: C, 60.99; H, 7.89; N, 7.28. [α]²⁵ _(D) =-4.00° (c 1.75, MeOH).

Example 50 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(1

50a. 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

To 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(S)-pyrrolidinyl-methoxy)pyridine from Example 33 (110 mg, 0.27 mmol) was added formalin (38%, 3.0 mL) and formic acid (88%, 1.5 mL). The mixture was refluxed for five hours then cooled to room temperature. Hydrochloric acid (36%, 0.3 mL) was added, and the mixture was extracted with Et₂ O (3×8 mL). The aqueous layer was heated under vacuum to dryness. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1 to afford an oil (72 mg, 83%). MS (CI/NH₃) m/z 330 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.70-2.10 (m, 4H), 2.38-2.40 (m, 1H), 2.51 (s, 3H), 2.65-2.76 (m, 1H), 3.10-3.19 (m, 1H), 3.96-4.10 (m, 2H), 6.96-7.04 (m, 1H), 7.39-7.44 (m, 2H), 7.53 (s, 1H), 7.52-7.60 (m, 1H), 8.05-8.08 (m, 1H), 8.63-8.67 (m, 1H).

50b. 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (70 mg, 0.21 mmol) in THF (3.0 mL) was added hydrogen chloride (1.0M in Et₂ O, 0.70 mL, 0.70 mmol). The precipitate formed was filtered, washed (Et₂ O) and vacuum-dried to afford the hydrochloride salt (79 mg, 94%). mp. 218°-222° C. MS (CI/NH₃) m/z 330 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz, presumed to be two rotomers, tentative assignment of one) δ1.85-2.48 (m, 4H), 2.97 (s, 3H), 3.15-3.32 (m, 1H), 3.65-4.01 (m, 2H), 4.16-4.43 (m, 2H), 7.05-7.11 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.38 (m, 1H), 7.74-7.79 (m, 1H), 8.13-8.19 (m, 2H), 8.55-8.5 (m, 2H). Anal. Calcd for C₁₈ H₂₀ N₃ OCl•2.2 HCl•1.0 MeOH: C, 51.62; H, 5.97; N, 9.51. Found: C, 51.60; H, 5.67; N, 9.24. [α]²⁵ _(D) =-5.7° (c 0.65, MeOH).

Example 51 5-phenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

51a. 1-Tosyl-(S)-pyrrolidinemethanol

(S)-Prolinol (Aldrich Chem. Co., 5.10 g, 0.05 mmol) p-toluenesulfonyl chloride (9.63 g, 0.05 mmol) and triethylamine (8.5 mL, 0.06 mmol) were dissolved in chloroform (50 mL), and the reaction mixture was stirred for 20 hours at room temperature. To the mixture was added water and aqueous saturated NaCO₃ to give a pH 8-9. This mixture was extracted with theyl acetate, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane 1:1 to afford the title compound. MS (DCI/NH₃) m/z 256 (M+H)⁺, 273 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 7.75 (d, J=2.5, 2H), 7.33 (d, J=2.5, 2H), 7.27 (s, 1H), 3.7-3.6 (m, 3H), 3.5-3.4 (m, 1H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 1H), 2.42 (s, 3H), 1.85-1.65 (m, 3H), 1.5-1.4 (m, 1H), 1.33-1.26 (m, 1H).

51b. 5-bromo-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine

To a suspension of 3,5-dibromopyridine (1.5 g, 6.05 mmol) and 60% NaH (307 mg, 7.7 mmol) in DMF (6 mL) was added 1-tosyl-2-(S)-pyrrolidinemethanol (1.4 g, 5.5 mmol), and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane 6:1 to afford the title compound (1.2 g).

51c. 5-phenyl-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine

5-bromo-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 51b (300 mg, 10.73 mmol), boric acid (107 mg, 10.88 mmol) and Pd(0) (26 mg) were mixed together in benzene (2 mL), and the mixture was heated at reflux for 16 hours. NaHCO₃ solution (2%, 1 mL) was added, and the mixture was extracted with chloroform. The CHCl₃ was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane 1:1 to afford the title compound (300 mg).

51d. 5-phenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine

The 5-phenyl-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine from the previous step was dissolved in HBr/HOAc, and the reaction was stirred at room temperature for 16 hours and at 40° C. for 4 hours. The volatiles were removed under vacuum, and the residue was chromatographed on a silica gel column, eluting with chloroform/methanol 10/1.5 to afford the title compound (57 mg). MS (DCI/NH₃) m/z 255 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.54-2.12 (m, 5H), 2.95-3.13 (m, 2H), 3.54-3.66 (m, 1H), 3.94-4.08 (m, 2H), 7.36-7.52 (m, 4H), 7.54-7.62 (m, 2H), 8.29 (d, J=3, 1H), 8.46 (d, J=2, 1H).

51e. 5-phenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The salt was prepared by treatment with HCl in ether, as described above, to give the rifle compound. mp. 134°-136° C. MS (DCI/NH₃) m/z 255 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 1.92-2.35 (m, 4H), 3.41-3.66 (m, 2H), 4.11-4.20 (m, 1H), 4.33 (dd, J=7.5, 10.5, 1H), 4.54 (dd, J=3.4, 10.6, 1H), 7.50-7.61 (m, 5H), 7.70-7.78 (m, 3H), 8.30 (d, J=2.7, 1H), 8.51 (d, J=1.7, 1H). Anal. Calcd for C₁₆ H₁₈ N₂ OCl•2 HCl: C, 58.72; H, 6.16; N, 8.56. Found: C, 58.62; H, 6.16; N, 8.88. [α]²⁵ _(D) =+13.67° (c 0.2, MeOH).

Example 52 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

Following the procedures of Example 51, except starting with the (R)-prolinol instead of the (S)-prolinol, the title compound was prepared. mp. 129°-131° C. MS (DCI/NH₃) m/z 255 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 1.92-2.37 (m, 5H), 3.44 (t, J=18, 2H), 4.13-4.22 (m, 1H), 4.37 (dd, J=7.4, 10.5, 1H), 4.59 (dd, J=3.4, 10.6, 1H), 7.56-7.63 (m, 5H), 7.71-7.75 (m, 2H), 8.05 (t, J=2.0, 1H), 8.39 (d, J=2.7, 1H), 8.60 (d, J=1.7, 1H). Anal. Calcd for C₁₆ H₁₈ N₂ OCl•2 HCl: C, 58.72; H, 6.16; N, 8.56. Found: C, 58.45; H, 6.24; N, 8.49. [α]²⁵ _(D) =-2.7° (c 0.3, MeOH).

Example 53 5-phenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine from Example 52 (150 mg, 0.59 mmol) was added formalin (38%, 5.0 mL) and formic acid (88%, 2.5 mL), and the mixture was refluxed for 16 hours. The reaction was quenched by the addition of saturated aqueous NaHCO₃. The mixture was extracted with CHCl₃, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl₃ /MeOH 10:1.5 to afford the base. The salt was prepared by treatment with HCl in ether, as described above, to give the title compound. mp. 89°-90 ° C. MS (DCI/NH₃) m/z 269 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.05-2.29 (m, 2H), 2.38-2.47 (m, 1H), 3.07 (s, 3H), 3.23-3.32 (m, 1H), 3.64-3.82 (m, 1H), 3.92-4.00 (m, 1H), 4.44 (dd, J=7.7, 11.0 (1H), 4.61 (dd, J=3.0, 11.2, 1H), 7.51-7.62 (m, 3H), 7.70-7.74 (m, 2H), 7.88 (s, 1H), 8.36 (br s, 1H), 8.56 (br s, 1H). Anal. Calcd for C₁₇ H₂₀ N₂ OCl•2 HCl•0.5 H₂ O: C, 58.29; H, 6.62; N, 8.00. Found: C, 58.16; H, 6.76; N, 8.18. [α]²⁵ _(D) =+9.2° (c 0.39, MeOH).

Example 54 Intermediate Compound 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

54a. 1-BOC-2-(S)-azetidinemethanol

(S)-Azeditinecarboxylic acid (Aldrich) was treated with di-t-butyl dicarbonate to give the 1-BOC-(S)-azeditinecarboxylic acid. This compound in turn was dissolved in anhydrous THF and brought to 0° C. with stirring. Borane/THF complex was added dropwise via syringe over a 10 minute period. The reaction mixture was stirred at room temperature for 1 hour, then the reaction was quenched slowly with saturated NaHCO₃ and stirred for an additional hour. The solvent was removed in vacuo, and the residue was diluted with H₂ O. The desired compound was extracted from the aqueous phase with Et₂ O (3×). The organic layer was then washed with brine (2×) dried (MgSO₄) and evaporated to afford the title compound.

54b. 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mmol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for for 10 minutes. Samples of 1-BOC-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol), prepared as described above, and 5-bromo-3-hydroxypyridine (1.505 g, 10.2 mmol) were added, and the reaction mixture was stirred for 40 hours at room temperature. The volatiles were removed under vacuum, and the residue was triturated with hexane. The hexane was removed, and the residue was chromatographed on a silica gel column, eluting with hexane:ether 10:1 to 10:2 to afford the title compound as a colorless oil (1.669 g). MS (CI/NH₃) m/z 344 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H).

Example 55 5-(5,5-Dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine citric acid salt

55a. 5-(5,5-Dimethyl-1,3-hexadienyl)-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridin

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine (600 mg, 1.59 mmol) in acetonitrile (5.0 mL) and triethylamine (4.5 mL) was added 5,5-dimethyl-1,3-hexadiene (228 mg), palladium acetate (39 mg) and tri-o-tolylphosphine (205 mg). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane 1:3 to afford the title compound (126 mg, 42% yield). MS (CI/NH₃) m/z 307 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.42 (s, 9H), 1.55 (s, 9H), 2.24-2.42 (m, 2H), 3.88 (t, J=7.5, 2H), 4.13 (dd, J=3, 7.5, 1H), 4.29-4.41 (m, 1H), 5.97 (d, J=15, 1H), 6.22 (dd, J=9, 15, 1H), 6.67-6.78 (m, 2H), 7.45 (br s, 1H), 8.95 (d, J=3.0, 1H).

55b. 5-(5,5-Dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine citrate

To a solution of the compound from step 55a (126 mg) in methylene chloride (1.5 mL) was added TFA (1.5 mL), and the mixture was stirred for 4 hours at room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 10:1 to afford the free base of the title compound (75 mg, 79% yield). MS (DCI/NH₃) m/z 307 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 2.22-2.51 (m, 3H), 3.50-3.60 (m, 1H), 3.68-3.83 (m, 1H), 4.01-4.14 (m, 2H), 4.27-4.42 (m, 1H), 5.96 (d, J=15 Hz, 1H), 6.22 (ddd, J=3.0, 7.5, 15 Hz, 1H), 6.70-6.75 (m, 2H), 7.41 (d, J=3.0 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H). This material was converted to the title compound by treatment with citric acid in ethanol. mp. 100°-102° C. MS (CI/NH₃) m/z 307 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.54-2.86 (m, 7h), 3.98-4.18 (m, 3H), 4.40-4.44 (m, 2H), 6.04 (d, J=15.4, 1H), 6.23-6.32 (m, 1H), 6.73 (d, J=15.8, 1H), 6.98 (dd, J=10.3, 15.1, 1H), 7.73 (d, J=3.0, 1H), 8.01 (d, J=3.0, 1H). Anal. Calcd for C₁₇ H₂₃ N₂ O•1.1 C₆ H₈ O₇ : C, 54.70; H, 6.19; N, 5.41. Found: C, 54.59; H, 5.93; N, 5.20. [α]²⁵ _(D) =+4.33° (c 0.1, MeOH).

Example 56 5-Phenyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

56a. 5-Phenyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (1.03 g, 3 mmol), phenylboronic acid (920 mg, 7.5 mmol), Pd(0) (100 mg) and Na₂ CO3 (4 mL of a 2M solution) were mixed in 20 mL of toluene, and the mixture was stirred at reflux for 3 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with chloroform:methanol 100:2, to afford 1.39 g of the title compound. MS (CI/NH₃) m/z 341 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.38 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.21 (m, 1H), 4.41 (m, 1H), 4.54 (m, 1H), 7.40 (m, 3H), 7.50 (m, 2H), 8.10 (m, 1H), 8.54 (m, 1H), 8.20 (m, 1H).

56b. 5-Phenyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

The BOC group was removed from the compound of step a by treatment with TFA in methylene chloride at 0° C. for 30 minutes to give the free base of the title compound. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The free base was chromatographed on a silica gel column, eluting with methanol:methylene chloride:NH₄ OH 10:100:0.5 to afford the title compound (550 mg). MS (CI/NH₃) m/z 241 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.47 (m, 2H), 3.68 (m, 1H), 3.87 (m, 1H), 4.18 (m, 2H), 4.52 (m, 1H), 7.45 (m, 4H), 7.56 (m, 2H), 8.28 (m, H), 8.47 (s, 1H). The base (111 mg) was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound (82.9 mg). MS (DCI/NH₃) m/z 241 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.68-2.77 (m, 2H), 4.08-4.29 (m, 2H), 4.42 (d, J=4.1 Hz, 1H), 4.98 (m, 1H), 7.45-7.56 (m, 3H), 7.57-7.68 (m, 3H), 8.28 (d, J=2.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H). Anal. Calcd for C₁₅ H₁₆ N₂ O•2 HCl•0.5 H₂ O: C, 55.91; H, 5.94; N, 8.69. Found: C, 55.83; H, 5.72; N, 8.80. [α]²⁵ _(D) =-6.00° (c 0.60, MeOH).

Example 57 5-Phenyl-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine dihydrochloride

To 5-phenyl-3-(2-(S)-azetidinylmethoxy)pyridine HCl from Example 56 (440 mg, 1.8 mmol) in water (7 mL) was added formalin (37%, 0.5 mL), formic acid (0.6 mL), and the pH was adjusted to 5. Then NaCNBH₃ (37 mg, 6.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to 9 with 10% NaOH, and the mixture was extracted with methylene chloride. The solvent was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:2-10 to afford the base (175 mg). MS (CI/NH₃) m/z 255 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.12 (m, 2H), 2.44 (s, 3H), 2.90 (m, 1H), 3.48 (m, 2H), 4.11 (m, 2H), 7.44 (m, 4H), 7.58 (m, 2H), 8.29 (m, 1H), 8.47 (m, 1H). The salt was prepared by treatment with HCl in ether, as described above, to give the title compound (47 mg). mp. 120°-122° C. MS (DCI/NH₃) m/z 255 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.61-2.79 (m, 2H), 3.02 (s, 3H), 4.31 (m, 1H), 4.51-4.64 (m, 2H), 4.80 (m, 2H), 7.60 (m, 3H), 7.74 (m, 2H), 8.00 (m, 1H), 8.41 (d, J=2.4, 1H), 8.60 (d, J=1.6, 1H). Anal. Calcd for C₁₆ H₁₈ N₂ O•2 HCl 0.4 H₂ O: C, 57.46; H, 6.27; N, 8.38. Found: C, 57.28; H, 6.41; N, 8.18. [α]²⁵ _(D) =-24.88° (c 0.44, MeOH).

Example 58 5-Hexynyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

58a. 5-Hexynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine (47752-235)

To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (180 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.05 mmol), copper (I) iodide (2 mg) and triethylamine (1.0 mL) in methylene chloride (3 mL) was added 1-hexyne (8.3 mL, 0.72 mmol). The mixture was refluxed overnight and cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane 1:1 to afford the title compound (102 mg, 56% yield). MS (CI/NH₃) m/z 379 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.96 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 1.46-1.69 (m, 4H), 2.20-2.40 (m, 2H), 2.44-2.56 (m, 2H), 3.83-3.92 (m, 2H), 4.06-4.15 (m, 1H), 4.26-4.38 (m, 1H), 4.45-4.57 (m, 1H), 7.34 (br s, 1H), 7.51-7.58 (m, 1H).

58b. 5-Hexynyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride (47752-250)

A solution of 5-hexynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 58a (102 mg, 0.26 mmol) in methylene chloride (2 mL) and TFA (1 mL) was stirred at room temperature for 3 hours. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with chloroform:methanol:NH₄ OH 10:1:0.1 to afford the free base of the title compound (73 mg, 96% yield). MS (DCI/NH₃) m/z 279 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 0.96 (t, J=7.0 Hz, 3H), 1.43-1.61 (m, 2H), 2.21-2.44 (m, 4H), 2.48 (t, J=7.5 Hz, 2H), 3.44-3.52 (m, 1H), 3.68-3.80 (m, 1H), 3.96-4.09 (m, 2H), 4.25-4.35 (m, 1H), 7.28 (d, J=3.0 Hz, 1H, 7.99 (d, J=3.0 Hz, 1H). The base was treated with HCl in ethanol to afford the hydrochloride salt (73 mg). mp 103°-105° C. MS (CI/NH₃) m/z 279 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.98 (t, J=7.4, 3H), 1.48-1.72 (m, 4H), 2.55-2.60 (m, 2H), 2.68-2.77 (m, 2H), 4.07-4.24 (m, 2H), 4.44-4.48 (m, 2H), 4.80-4.99 (m, 1H), 7.66 (d, J=2.7, 1H), 8.14 (d, J=3.1, 1H). Anal. Calcd for C₁₅ H₁₉ N₂ O•1.6 HCl: C, 53.44; H, 6.16; N, 8.31. Found: C, 53.81; H, 5.77; N, 8.43. [α]²⁵ _(D) =-7.5° (c 0.2, MeOH).

Example 59 5-(2-(4-Pyridinyl)vinyl)-3-(2-(S)-azetidinylmethoxy)pyridine trihydrochloride

59a. 5-(2-(4-Pyridinyl)vinyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (1.03 g, 3.0 mmol) in acetonitrile (20 mL) and triethylamine (12.5 mL) was added 4-vinylpyridine (0.65 mL, 6 mmol), palladium acetate (125 mg, 0.56 mmol) and tri-o-tolylphosphine (625 mg). The mixture was heated at reflux for 16 hours. The solvent was removed, and the residue was washed with saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO₄), and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 1:2 to 0:1 to afford the title compound (760 mg, 69%). MS (CI/NH₃) m/z 368 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.43 (s, 9H), 2.35 (m, 2H), 3.90 (m, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 4.55 (m, 1H), 7.10 (m, 1H), 7.2 (m, 1H), 7.38 (m, 2H), 7.45 (br s, 1H), 8.29 (m, 1H), 8.37 (s, 1H), 8.61 (m, 2H).

59b. 5-(2-(4-Pyridinyl)vinyl)-3-(2-(S)-azetidinylmethoxy)pyridine trihydrochloride

A solution of the compound from step 59a (130 mg, 0.35 mmol) in methylene chloride (2 mL) and TFA (0.9 mL) was stirred for 30 minutes at 0° C. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The free base was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 10:1:0 to 10:1:0.3 to afford the pure compound (75 mg). MS (CI/NH₃) m/z 268 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.54 (m, 2H), 3.56 (m, 1H), 3.76 (m, 1H), 4.14 (m, 2H), 4.38 (m, 1H), 7.04 (m, 1H), 7.22 (m, 1H), 7.40 (m, 3H), 8.25 (m, 1H), 8.36 (s, 1H), 8.63 (m, 2H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound (50 mg). mp. 98°-100° C. MS (CI/NH₃) m/z 268 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.65 (m, 2H), 4.12 (m, 2H), 4.40 (d, J=4.4 Hz, 1H), 4.78 (m, 1H), 4.95 (m, 1H), 7.20 (d, J=16.2 Hz, 1H), 7.38 (d, J=16.2 Hz, 1H), 7.51 (d, J=6.4 Hz, 2H), 7.62 (m, 1H), 8.21 (m, 1H), 8.32 (m, 1H), 8.45 (d, J=5.8 Hz, 2H). Anal. Calcd for C₁₆ H₁₇ N₃ O•0.8 HCl•0.1 H₂ O: C, 64.42; H, 6.08; N, 14.09. Found: C, 64.68; H, 5.98; N, 13.70. [α]²⁵ _(D) =-18.38° (c 0.98, MeOH).

Example 60 5-(2-(4-Pyridinyl)ethyl)-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

60a. 5-(2-(4-Pyridinyl)ethyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To a solution of 5-(2-(4-pyridinyl)vinyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 59a (188 mg, 0.51 mmol) in methanol (10 mL) was added Pd/C (20 mg), and the mixture was stirred at room temperature for 40 hours. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 10:2 to 10:5 to afford the title compound (154 mg). MS (CI/NH₃) m/z 370 (M+H)⁺. ¹ H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.10 (m, 1H), 4.28 (m, 1H), 4.50 (m, 1H), 7.02 (m, 1H), 7.02 (m, 1H), 7.08 (m, 2H), 8.06 (m, 1H), 8.20 (m, 1H), 8.51 (m, 2H).

60b. 5-(2-(4-Pyridinyl)ethyl)-3-(1-2-(S)-azetidinylmethoxy)pyridine

A solution of the compound from step 60a (154 mg, 0.42 mmol) in methylene chloride (2 mL) and TFA (1.2 mL) was stirred for 30 minutes at 0° C. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 10:1:0 to 10:1:0.3 to afford the free base of the title compound. MS (CI/NH₃) m/z 270 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.42 (br s, 2H), 2.92 (s, 4H), 3.62 (m, 1H), 3.83 (m, 1H), 4.09 (m, 2H), 4.44 (m, 1H), 6.96 (s, 1H), 7.08 (m, 2H), 8.08 (br, 1H), 8.18 (m, 1H), 8.50 (br, 1H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound. MS (CI/NH₃) m/z 270 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.65 (m, 2H), 3.05 (m, 4H), 4.10 (m, 2H), 4.33 (d, J=4.1 Hz, 2H), 4.91 (m, 1H), 7.23 (m, 3H), 7.99 (s, 1H), 8.15 (s, 1H), 8.37 (m, 2H). Anal. Calcd for C₁₆ H₁₉ N₃ O•1.5 HCl•0.1 EtOH•0.1 H₂ O: C, 59.11; H, 6.56; N, 12.60. Found: C, 59.37; H, 6.25; N, 12.60. [α]²⁵ _(D) =-4.13° (c 0.92, MeOH).

Example 61 5-(2-(4-Pyridinyl)vinyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine trihydrochloride

A sample of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (130 mg, 0.35 mmol) was dissolved in 2 mL of formic acid and 4 mL of formalin, and the mixture was heated at 70° C. for 16 hours. The mixture was basified with saturated saturated sodium bicarbonate, then extracted with methylene chloride. The organic layer was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methelene chloride:methanol 10:1 to afford the free base of the title compound (58 mg). MS (CI/NH₃) m/z 368 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.42 (s, 8H), 2.35 (m, 2H), 3.91 (m, 2H), 4.20 (m, 1H), 4.42 (m, 1H), 4.55 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.38 (m, 2H), 7.45 (s, 1H), 8.29 (m, 1H), 8.37 (s, 1H), 8.62 (m, 2H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound. MS (CI/NH₃) m/z 282 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.64-2.78 (m, 2H), 3.02 (s, 3H), 4.04 (m, 1H), 4.31 (m, 1H), 4.56-4.69 (m, 2H), 7.61 (d, J=16.3 Hz, 1H), 7.85 (d, J=16.3 Hz, 1H), 8.20 (d, J=6.8 Hz, 2H), 8.27 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.68 (s, 1H), 8.73 (d, J=6.4 Hz, 2H). Anal. Calcd for C₁₇ H₁₉ N₃ O•3.7 HCl•0.3 EtOH: C, 49.85; H, 5.91; N, 9.58. Found: C, 50.11; H, 6.09; N, 9.24. [α]²⁵ _(D) =-16.83° (c 0.60, MeOH).

Example 62 5-(2-(4-Pyridinyl)ethyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine dihydrochloride

A sample of 5-(2-(4-Pyridinyl)ethyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 60a (220 mg, 0.60 mmol) was dissolved in 4 mL of formic acid and 8 mL of formalin, and the mixture was heated at 70° C. for 16 hours. The mixture was basified with saturated saturated sodium bicarbonate, then extracted with methylene chloride. The organic layer was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methelene chloride:methanol 10:1 to afford the free base of the title compound (71 mg). MS (CI/NH₃) m/z 284 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.08 (m, 2H), 2.40 (s, 3H), 2.88 (m, 1H), 3.36 (m, 1H), 3.46 (m, 1H), 3.98 (m, 2H), 6.98 (m, 1H), 7.08 (m, 2H), 8.04 (s, 1H), 8.17 (m, 1H), 8.49 (m, 2H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound. mp 105°-107° C. MS (CI/NH₃) m/z 284 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.67 (m, 2H), 2.99 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 3.28 (t, J=7.1 Hz, 2H), 4.00 (m, 1H), 4.28 (m, 1H), 4.36-4.49 (m, 2H), 4.80 ((m, 1H), 7.46 (s, 1H), 7.74 (d, J=6.1 Hz, 1H), 8.02 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 8.57 (d, J=6.2 Hz, 2H). Anal. Calcd for C₁₇ H₂₁ N₃ O•2.4 HCl•0.1 EtOH: C, 55.25; H, 6.50; N, 11.11. Found: C, 55.27; H, 6.43; N, 10.76. [α]²⁵ _(D) =-8.32° (c 0.62, MeOH).

Example 63 5-octynyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

63a. 5-octynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (450 mg, 1.3 mmol) in 10 mL of methylene chloride was added triethylamine (0.6 mL), Pd(PPh₃)₂ Cl₂ (25 mg), CuI (a catalytic amount) and 1-octyne (0.37 mL, 0.26 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with methylene chloride, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The residue was purified by chromatography, eluting with 1 to 2% methanol in methylene chloride to afford the title compound (438 mg). MS (CI/NH₃) m/z 373 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.91 (m, 3H), 1.32 (m, 2H), 1.41 (s, 9H), 1.44 (m, 2H), 1.61 (m, 2H), 2.30 (m, 2H), 2.41 (m, 2H), 3.88 (m, 2H), 4.11 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.23 (m, 1H), 8.23 (br s, 2H).

63b. 5-octynyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

A sample of 5-octynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 63a in methylene chloride (3 mL) and TFA (2 mL) was stirred for 30 minutes at 0° C. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 10:5 to 10:11 to afford the free base of the title compound (178 mg). MS (CI/NH₃) m/z 273 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.45 (m, 2H), 1.62 (m, 2H), 2.40 (m, 2H), 2.53 (m, 2H), 3.80 (m, 1H), 3.96 (m, 1H), 4.19 (m, 2H), 4.62 (m, 1H), 7.22 (m, 1H), 8.20 (m, 2H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound. mp 88°-90° C. MS (CI/NH₃) m/z 273 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.90 (m, 3H), 1.33 (m, 4H), 1.46 (m, 2H), 1.64 (m, 2H), 2.50 (t, J=2.9 Hz, 2H), 2.71 (m, 2H), 4.05-4.22 (m, 2H), 4.49 (d, J=4.4 Hz, 2H), 4.98 (m, 1H), 7.99 (m, 1H), 8.34 (s, 1H), 8.39 (d, J=2.6 Hz, 1H). Anal. Calcd for C₁₇ H₂₄ N₂ O•2.8 HCl: C, 54.53; H, 7.21; N, 7.48. Found: C, 54.25; H, 7.12; N, 7.63. [α]²⁵ _(D) =-9.64° (c 2.08, MeOH).

Example 64 5-octynyl-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine dihydrochloride

A sample of 5-octynyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 63a (175 mg, 0.47 mmol) was dissolved in 3.5 mL of formic acid and 7 mL of formalin, and the mixture was heated at 70° C. for 16 hours. The mixture was basified with saturated saturated sodium bicarbonate, then extracted with methylene chloride. The organic layer was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methelene chloride:methanol 10:3 to 10:8 to afford the free base of the title compound (54.2 mg). MS (CI/NH₃) m/z 287 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.44 (m, 2H), 1.61 (m, 2H), 2.08 (m, 2H), 2.39 (s, 3H), 2.42 (m, 2H), 2.88 (m, 1H), 3.42 (m, 2H), 4.00 (m, 2H), 7.18 (m, 1H), 8.20 (m, 2H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound. MS (CI/NH₃) m/z 287 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ0.86 (m, 2H), 1.32 (m, 3H), 1.46 (m, 2H), 1.63 (m, 2H), 2.50 (t, J=6.9 Hz, 2H), 2.63-2.74 (m, 2H), 2.99 (s, 3H), 4.03 (m, 1H), 4.27 (m, 1H), 4.53 (m, 2H), 4.80 (m, 1H), 7.98 (s, 1H), 8.39 (s, 1H), 8.43 (d, J=2.4 Hz, 1H).

Anal. Calcd for C₁₈ H₂₆ N₂ O•2.1 HCl: C, 59.56; H, 7.80; N, 7.72. Found: C, 59.36; H, 7.83; N, 7.72. [α]²⁵ _(D) =-16.16° (c 0.76, MeOH).

Example 65 5-(3-aminophenyl)-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

65a. 5-(3-aminophenyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (400 mg, 1.2 mmol), 3-aminophenylboronic acid (361 mg, 2.3 mmol, Aldrich Chem. Co.), Pd(0) (35 mg) and Na₂ CO3 (1.5 mL of a 2M solution) were mixed in 8 mL of toluene, and the mixture was stirred at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with exane:ether 1:1, to afford 178 mg of the title compound. MS (CI/NH₃) m/z 356 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H), 3.92 (m, 2H), 4.20 (m, 1H), 4.38 (m, 1H), 4.55 (m, 1H), 6.72 (m, 1H), 6.88 (s, 1H), 6.97 (m, 1H), 7.44 (m, 2H), 8.31 (m, 1H), 8.44 (m, 1H).

65b. 5-(3-aminophenyl)-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

The BOC group was removed from the compound of step 65a (157 mg) by treatment with TFA in methylene chloride at 0° C. for 30 minutes to give the free base of the title compound. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 10:1:0.03 to afford the free base of the title compound (75 mg, 67% yield). MS (CI/NH₃) m/z 256 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.30 (m, 1H), 2.42 (m, 1H), 3.79 (m, 2H), 4.10 (m, 2H), 4.32 (m, 1H), 6.88 (m, 1H), 6.97 (m, 1H), 7.23 (m, 1H), 7.48 (s, 1H), 8.28 (m, 1H), 8.43 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound. mp 85°-87° C. MS (DCI/NH₃) m/z 256 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.56 (m, 2H), 3.84 (m, 1H), 4.34 (d, J=5.1 Hz, 1H), 4.72 (m, 2H), 6.93 (m, 1H), 7.10 (m, 2H), 7.36 (m, 1H), 7.61 (m, 1H), 8.25 (m, 1H), 8.39 (m, 1H). Anal. Calcd for C₁₅ H₁₇ N₃ O•0.5 HCl: C, 65.86; H, 6.45; N, 15.36. Found: C,65.84; H, 6.26; N, 15.32. [α]²⁵ _(D) =-12.36° (c 0.96, MeOH).

Example 66 Intermediate compound 5-Bromo-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

66a. 5-Bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine (50722-136)

To a solution of diethyl azodicarboxylate (1.52 mL, 9.6 mmol) in THF (56 mL) was added triphenylphosphine (2.52 g, 9.6 mmol) at 0° C., and the reaction mixture was stirred for half an hour. 1-BOC-2-(S)-azetidinemethanol (1.44 g, 7.7 mmol) and 5-bromo-6-chloropyridine-3-ol (1.4 g, 6.4 mmol; prepared according to V. Koch and S. Schnatterer, Synthesis 1990, 499-501)) were then added. The reaction mixture was slowly warmed up to room temperature overnight. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with chloroform:methanol 100:1 to afford the title compound. MS (DCI/NH₃) m/z 377, 379 (M+H)⁺.

66b. 5-Bromo-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride (50722-141)

To 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 66a (360 mg, 0.95 mmol) was added TFA in methylene chloride at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 10:1:0.1 to afford to give the free base of the title compound. The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound (224 mg). mp 168°-169° C. MS (DCI/NH₃) m/z 277, 279 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.69 (dd, J=7.0, 8.5, 2H), 4.06-4.20 (m, 3H), 4.43 (d, J=4.5, 2H), 4.91-4.99 (m, 1H), 7.94 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H). Anal. Calcd for C₉ H₁₀ N₂ OBrCl•0.9 HCl: C, 34.83; H, 3.54; N, 9.03. Found: C, 34.85; H, 3.56; N, 8.82. [α]²⁵ _(D) =-4.81° (c 0.13, MeOH).

Example 67 5-Phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

67a. 5-Phenyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (375 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmol) and Pd(0) (35 mg) were mixed together in toluene (2 mL), and the mixture was heated at reflux for 16 hours. NaHCO₃ solution (2%, 1 mL) was added, and the mixture was extracted with chloroform. The CHCl₃ was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane 1:1 to afford the title compound (280 mg). MS (DCI/NH₃) m/z 375 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.40 (s, 9H), 2.33-2.43 (m, 2H), 3.29 (t, J=7.5 Hz, 2H), 4.15 (dd, J=2.5, 7.5 Hz, 1H), 4.32-4.42 (m, 1H), 4.48-4.57 (m, 1H), 7.25-7.29 (m, 4H), 7.28 (d, J=2 Hz, 1H), 7.42-7.48 (m, 5H), 8.12 (d, J=3 Hz, 1H).

67b. 5-Phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

To 5-phenyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 67a (380 mg) was added TFA in methylene chloride at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO₃ to pH 8, then extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 10:1:0.1 to afford to give the free base of the title compound. MS (CI/NH₃) m/z 275 (M+H)⁺, 277 (M+2H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.21-2.46 (m, 2H), 3.41-3.50 (m, 1H), 3.73 (dd, J=7.5, 8.0 Hz, 1H), 4.0-4.12 (m, 2H), 4.25-4.35 (m, 1H), 7.26 (d, J=3 Hz, 1H), 7.41-7.48 (m, 5H), 8.09 (d, J=3 Hz, 1H). The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound (256 mg). mp 148°-150° C. MS (DCI/NH₃) m/z 275 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.66-274 (m, 2H), 4.06-4.21 (m, 3H), 4.46 (d, J=4.1, 2H), 4.92-5.01 (m, 1H), 7.50-7.59 (m, 5H), 7.60 (d, J=3.0, 1H), 8.20 (d, J=3.0, 1H).

Anal. Calcd for C₁₅ H₁₅ N₂ OCl•2 HCl: C, 51.82; H, 4.93; N, 8.06. Found: C, 52.10; H, 5.29; N, 7.70. [α]²⁵ _(D) =+7.5° (c 0.16, MeOH).

Example 68 5-Phenyl-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine hydrochloride

To 5-phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine from Example 67 (100 mg, 0.36 mmol) in ethanol (3 mL) was added formalin (37%, 0.5 mL) and formic acid (0.25 mL), and the pH was adjusted to 6. Then NaCNBH₃ (70 mg) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and saturated with K2CO3. The mixture was extracted with chloroform. The solvent was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 10:1 to afford the free base of the title compound. MS (DCI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.05-2.14 (m, 2H), 2.40 (s, 3H), 2.32-2.44 (m, 1H), 3.34-3.51 (m, 2H), 4.44 (d, J=7.5 Hz, 2H), 7.26 (d, J=3 Hz, 1H), 8.09 (d, J=3 Hz, 1H). The salt was prepared by treatment with HCl in ether, as described above, to give the title compound. mp 187°-188° C. MS (DCI/NH₃) m/z 289 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.60-2.71 (m, 2H), 2.99 (s, 3H), 3.94-4.12 (m, 1H), 4.18-4/33 (m, 1H), 4.47-4.55 (m, 3H), 7.57 (m, 5H), 7.60 (d, J=3.0 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₆ H₁₇ N₂ OCl•HCl•0.5 H₂ O: C, 57.50; H, 5.73; N, 8.38. Found: C, 57.38; H, 5.53; N, 8.35. [α]²⁵ _(D) =+15° (c 0.11, MeOH).

Example 69 5-Phenyl-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

69a. 5-Bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

Following the procedure of Example 23, except substituting 1-BOC-(R)-pyrrolidinemethanol for the 1-BOC-(S)-pyrrolidinemethanol the thereof, the title compound was prepared. MS (CI/NH₃) m/z 391/393 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ01.65-2.05 (m, 4H), 3.20-3.35 (m, 2H), 3.95-4.15 (m, 3H), 7.98 (d, J=2.9 Hz, 1H), 8.21 (d, J=2.9 Hz, 1H).

69b. 5-Phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine and 5-6-diphenyl-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (784 mg, 2 mmol), phenylboronic acid (610 mg, 5 mmol), Na₂ CO₃ (3 mL) and Pd(0) (70 mg) were mixed together in toluene (20 mL), and the mixture was heated at reflux for 4 hours. The mixture was extracted with chloroform. The CHCl₃ was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate 100:5 to 100:25 to afford the title compounds. For the mono-phenyl compound: MS (DCI/NH₃) m/z 390 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.43 (s, 9H), 1.88 (m, 1H), 2.04 (m, 2H), 3.37 (m, 2H), 3.37 (m, 2H), 3.89 (br s, 1H), 4.01 (br s, 1H), 4.15 (m, 2H), 7.46 (s, 5H), 7.47 (m, 1H), 8.09 (m, 1H). For the diphenyl compound: MS (DCI/NH₃) m/z 431 (M+H)⁺ ¹ H NMR (CDCl₃, 300 MHz) δ1.46 (s, 9H), 1.89 (m, 1H), 2.07 (m, 2H), 34.2 (br s, 2H), 3.93 (br s, 1H), 4.07 (br s, 1H), 4.23 (m, 2H), 7.20 (m, 5H), 7.28 (m, 6H), 8.40 (m, 1H).

69c. 5-Phenyl-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine hydrochloride

To the 5-phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from step 69b (262 mg) was added formalin (37%, 0.5 mL) and formic acid (0.25 mL), and the mixture was heated at 70° C. for 3 hours. The solvent was removed, and to the residue was added solid NaHCO₃. When pH 7-8 was achieved, the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 100:10:0.04 to afford to give the free base of the title compound (200 mg). MS (DCI/NH₃) m/z 303 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.98 (m, 2H), 2.10 (m, 1H), 2.22 (m, 1H), 2.71 (m, 1H), 2.78 (s, 3H), 3.27 (m, 1H), 3.60 (m, 1H), 4.18 (m, 1H), 4.47 (m, 1H), 7.46 (m, 5H), 8.10 (m, 1H), 8.30 (br s, 1H). The base was converted to the salt by treatment with HCl in THF to give the title compound. MS (DCI/NH₃) m/z 303 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 2.05-2.17 (m, 2H), 2.19-2.27 (m, 1H), 2.35-2.45 (m, 1H), 3.04 (s, 3H), 3.30 (m, 1H), 3.74 (m, 1H), 3.94 (m, 1H), 4.37 (dd, J=6.1, 11.2 Hz, 1H), 4.54 (dd, J=3.3, 11.2 Hz, 1H), 7.56 (m, 6H), 8.15 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₇ H₁₉ N₂ OCl•1.1 HCl: C, 59.55; H, 5.91; N, 8.17. Found: C, 59.74; H, 6.04; N, 8.14. [α]²⁵ _(D) =+7.17° (c 1.11, MeOH).

Example 70 5-Phenyl-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine hydrochloride

To the 5-phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from Example 69b (164 mg) was added HCl in dioxane (3 mL). The mixture was stirred at room temperature for 40 hours. The solvent was removed under vacuum at 50° C., and the residue was triturated with ether. The solid was dried under high vacuum to afford the title compound. mp 178°-180° C. MS (DCI/NH₃) m/z 289 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₆ H₁₇ N₂ OCl•1.2 HCl: C, 57.79; H, 5.52; N, 8.42. Found: C, 57.73; H, 6.5.58; N, 8.27. [α]²⁵ _(D) =-10.94° (c 0.64, MeOH).

Example 71 5,6-Diphenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

To the 5,6-diphenyl-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from Example 69b (140 mg) was added HCl in dioxane (3 mL). The mixture was stirred at room temperature for 40 hours. The solvent was removed under vacuum at 50° C., and the residue was triturated with ether. The solid was dried under high vacuum to afford the title compound. MS (DCI/NH₃) m/z 331 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.97.-2.20 (m, 3H), 2.33 (m, 1H), 3.43 (t, J=7.2 Hz, 1H), 3.74 (m, 1H), 4.21 (m, 1H), 4.48 (m, 1H), 4.68 (dd, J=3.4, 10.5 Hz, 1H), 7.27-7.55 (m, 10H), 8.23 (d, J=2.7 Hz, 1H), 8.55 (d, J=2.7 Hz, 1H). Anal. Calcd for C₂₂ H₂₂ N₂ O•2.4 HCl•0.5 H₂ O: C, 61.89; H, 6.00; N, 6.56. Found: C, 62.04; H, 6.17; N, 6.03. [α]²⁵ _(D) =-2.36° (c 1.95, MeOH).

Example 72 5,6-Diphenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

To the 5,6-diphenyl-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine compound from Example 69b (195 mg) was added formalin (37%, 6 mL) and formic acid (3mL), and the mixture was heated at 70° C. for 4 hours. The solvent was concentrated, and to the residue was added solid NaHCO₃. When pH 7-8 was achieved, the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH₄ OH 100:0.04 to afford to give the free base of the title compound (144 mg, 93% yield). MS (DCI/NH₃) m/z 345 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.02 (m, 3H), 2.19 (m, 1H), 2.67 (m, 1H), 2.67 (s, 3H), 3.17 (m, 1H), 3.50 (m, 1H), 4.19 (m, 1H), 4.42 (m, 1H), 7.19 (m, 5H), 7.28 (m, 5H), 8.32 (s, 1H). The base was converted to the salt by treatment with hydrogen chloride in THF to give the title compound. MS (DCI/NH₃) m/z 345 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 2.08-2.20 (m, 2H), 2.20-2.26 (m, 1H), 2.45-2.47 (m, 1H), 3.09 (s, 3H), 3.29 (m, 1H), 3.74 (m, 1H 4.02 (m, 1H), 4.37 (m, 1H), 7.27-7.55 (m, 10H), 8.23 (d, J=2.7 Hz, 1H), 8.56 d, J=2.7 Hz, 1H). Anal. Calcd for C₂₃ H₂₄ N₂ O•2.2 HCl•0.5 H₂ O: C, 63.70; H, 6.32; N, 6.46. Found: C, 63.68; H, 6.13; N, 6.68. [α]²⁵ _(D) =+12.30° (c 3.25, MeOH).

Examples 73 Intermediate Compound 5-bromo-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (150 mg) was stirred with HCl in dioxane (3 mL) at room temperature for 16 hours. The precipitate formed was triturated with ether, and the solid was dried under high vacuum to afford the title compound (99.2 mg). mp 230° C. MS (CDI/NH₃) m/z 291/293 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.89-2.02 (m, 1h), 2.05-2.21 (m, 2H), 2.21-2.35 (m, 1H), 3.42 (t, J=7.2 Hz, 2H), 4/12 (m, 1H)), 4.25 (dd, J=7.8, 10.5 Hz, 1H), 4.47 (dd, J=3.2, 10.5 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H). Anal. Calcd for C₁₀ H₁₂ N₂ OBrCl•2 HCl: C, 36.61; H, 3.99; N, 8.54. Found: C, 36.69; H, 3.91; N, 8.41. [α]²⁵ _(D) =-14.80° (c 0.25, MeOH).

Example 74 Intermediate Compound 5-bromo-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine hydrochloride

To 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 69a (210 mg, 0.54 mmol) was added formalin (37%, 7 mL) and formic acid (3.5 mL), and the mixture was heated at 70° C. for 2.5 hours. The solvent was concentrated, and solid NaHCO₃ was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:5-100:10 to afford to give the free base of the title compound (110 mg, 67% yield). MS (DCI/NH₃) m/z 305/307 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.68 (m, 3H), 2.02 (m, 1H), 2.32 (m, 1H), 2.48 (s, 3H), 2.67 (m, 1H), 3.12 (m, 1H), 3.96 (m, 2H), 7.52 (m, 1H), 8.06 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in THF to give the title compound. MS (DCI/NH₃) m/z 305/207 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 2.20-2.17 (m, 2H), 2.18-2.31 (m, 1H), 2.32-2.47 (m, 1H), 3.03 (s, 3H), 3.27 (m, 1H), 3.73 (m, 1H), 3.96 (m, 1H), 4.36 (dd, J=6.1, 11.2 Hz, 1H), 4.53 (dd, J=3.1, 11.2 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H). Anal. Calcd for C₁₁ H₁₄ N₂ OBrCl•1.1 HCl: C, 38.22; H, 4.40; N, 8.10. Found: C, 37.95; H, 4.81; N, 7.76. [α]²⁵ _(D) =+11.06° (c 0.24, MeOH).

Example 75 5-(3-aminophenyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

75a. 5-(3-aminophenyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (520 mg, 1.33 mmol) and 3-aminophenylboronic acid (310 mg, 2.0 mmol) in toluene (8mL) was added Pd(0) (50 mg) and Na₂ CO3 (2.5 mL of a 2M solution), and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on a silica gel column, eluting with chloroform:ether 100:5-100:4 to afford 160 mg of the title compound. MS (DCI/NH₃) m/z 404 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.44 (s, 9H), 1.88 (m, 1H), 2.03 (m, 2H), 3.37 (m, 2H), 3.76 (m, 2H), 4.16 (m, 2H), 6.75 (m, 2H), 6.82 (m, 1H), 7.22 (m, 2H), 8.08 (m, 1H).

75b. 5-(3-aminophenyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 75a was stirred with HCl in dioxane at room temperature. The precipitate formed was triturated with ether, and the solid was dried under high vacuum to afford the title compound. MS (DCI/NH₃) m/z 304 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 1.92-2.02 (m, 1H), 2.07-2.18 (m, 2H), 2.25-2.34 (m, 1H), 3.42 (t, J=7.3 Hz, 2H), 4.13 (m, 1H), 4.28 (dd, J=7.6, 10.8 Hz, 1H), 4.51 (dd, J=3.4, 10.5 Hz, 1H), 7.51-7.71 (m, 5H), 8.17 (d, J=3.1 Hz, 1H). Anal. Calcd for C₁₆ H₁₈ N₃ OCl•2 HCl•1.7 H₂ O: C, 51.01; H, 5.35; N, 11.15. Found: C, 50.75; H, 5.28; N, 10.95. [α]²⁵ _(D) =-13.95° (c 0.38, MeOH).

Example 76 5-(4-chlorophenyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine hydrochloride

76a. 5-(4-chlorophenyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (460 mg, 1.2 mmol) and 4-chlorophenylboronic acid (225 mg, 1.44 mmol) in toluene (10 mL) was added Pd(0) (40 mg) and Na₂ CO3 (1.2 mL of a 2M solution), and the mixture was heated at reflux for 1.5 hours. The solvent was removed under vacuum, and the residue was purified by chromotography on a silica gel column, eluting with hexane:ether 100:10-100:30 to afford of the title compound (345 mg, 68% yield). MS (DCI/NH₃) m/z 423 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.45 (s, 9H), 1.89 (m, 2H), 2.03 (m, 2H), 3.37 (m, 2H), 4.00 (m, 1H), 4.15 (m, 2H), 7.42 (m, 6H), 8.10 (m, 2H).

76b. 5-(4-chlorophenyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine

To 5-(4-chlorophenyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 76aa (340 mg, 0.8 mmol) was added formalin (37%, 10 mL) and formic acid (5 mL), and the mixture was heated at 70° C. for 2.5 hours. The solvent was concentrated, and solid NaHCO₃ was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:5-100:10 to afford to give the free base of the title compound (255 mg, 94% yield). MS (DCI/NH₃) m/z 337 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.80-2.40 (m, 4H), 2.52 (m, 1H), 2.65 (s, 3H), 2.98 (m, 1H), 3.38 (m, 1H), 4.08 (m, 1H), 4.28 (m, 1H), 7.23 (m, 1H), 7.42 (m, 4H), 8.10 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in ether/THF to give the title compound. mp 176°-178° C. MS (DCI/NH₃) m/z 337 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 2.06-2.16 (m, 2H), 2.19-2.23 (m, 1H), 2.38-2.41 (m, 1H), 3.03 (s, 3H), 3.24 (m, 1H), 3.74 (m, 1H), 3.91 (m, 1H), 4.36 (dd, J=6.1, 11.2 Hz, 1H), 4.54 (dd, J=3.1, 11.2 Hz, 1H), 7.49-7.57 (m, 5H), 8.14 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₇ H₁₈ N₂ OCl₂ •1.3 HCl: C, 53.08; H, 5.06; N, 7.28. Found: C, 52.93; H, 5.17; N, 7.33. [α]²⁵ _(D) =+7.33° (c 2.25, MeOH).

Example 77 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

77a. 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

A solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (480 mg, 1.2 mmol), 5-(5,5-dimethyl-1,3-hexadiene (200 mg, 1.8 mmol), Pd(OAc)₄ (25 mg), tris(o-tolyl)phosphine (125 mg), and triethylamine (2.5 mL) in acetonitrile (5 mL) was sealed in a tube and headed at 100° C. for 4 days. The solution was diluted with ethyl acetate, and the mixture was extracted with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromographed on a silica gel column, eluting with hexane:ether 100:5-100:15 to afford the title compound (135 mg, 43% yield). MS (DCI/NH₃) m/z 421 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.08 (s, 9H), 1.48 (s, 9H), 1.89 (m, 2H), 2.00 (m, 2H), 3.38 (m, 2H), 3.95 (m, 1H), 4.13 (m, 1H), 4.23 (m, 1H), 5.99 (m, 1H), 6.22 (m, 1H), 6.71 (m, 1H), 6.95 (m, 1H), 7.74 (br s, 1H).

77b. 5-5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

This compound from step 77a was deprotected and converted to the salt by treatment with hydrogen chloride in ether/THF to afford the title compound. mp 190°-192° C. MS (DCI/NH₃) m/z 321 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.08 (s, 9H), 1.92-2.02 (m, 1H), 2.06-2.19 (m, 2H), 2.22-2.32 (m, 1H), 3.39 (m, 2H), 4.13 (m, 1H), 4.25 (m, 1H), 4.47 (m, 1H), 6.13 (d, J=15.2 Hz, 1H), 6.37 (dd, J=10.2, 15.1 Hz, 1H), 6.77 (d, J=14.9 Hz, 1H), 6.96 (dd, J=10.2, 15.3 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H). Anal. Calcd for C₁₈ H₂₅ N₂ OCl•2 HCl: C, 55.90; H, 6.91; N, 7.11. Found: C, 54.87; H, 7.12; N, 6.85. [α]²⁵ _(D) =-6.67° (c 0.40, MeOH).

Example 78 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 77a (145 mg, 0.34 mmol) was added formalin (37%, 4 mL) and formic acid (2 mL), and the mixture was heated at 70° C. for 3 hours. The solvent was concentrated, and solid NaHCO₃ was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromotographed on a silica gel column, eluting with methylene chloride:methanol 100:4 to afford to give the free base of the title compound (72.5 mg, 66% yield). MS (DCI/NH₃) m/z 335 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.10 (s, 9H), 1.77 (m, 2H), 2.00 (m, 1H), 2.28 (m, 1H), 2.45 (m, 3H), 2.70 (m, 1H), 3.10 (m, 1H), 3.43 (m, 1H), 4.00 (m, 1H), 4.38 (m, 1H), 5.95 (m, 1H), 6.20 (m, 1H), 6.70 (m, 2H), 7.38 (m, 1H), 7.93 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in ether/THF to give the title compound. mp 194° C. (dec). MS (DCI/NH₃) m/z 335 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.07 (s, 9H), 1.78-2.05 (m, 2H), 2.17-2.28 (m, 1H), 2.90 (dd, J=5.1, 31.9 Hz, 3H), 3.12 (m, 1H), 3.50 (m, 3H), 4.41 (m, 2H), 6.04 (d, J=15.6 Hz, 1H), 6.30 (dd, J=10.2, 15.2 Hz, 1H), 6.70 (d, J-15.6 Hz, 1H), 7.10 (ss, J=10.2, 15.6 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H), 8.06 (d, J=3.1 Hz, 1H).

Anal. Calcd for C₁₉ H₂₇ N₂ OCl•1.7 HCl•0.8 Et₂ O: C, 58.45; H, 8.11; N, 6.14. Found: C, 58.58; H, 8.11; N, 5.85. [α]²⁵ _(D) =+6.95° (c 0.71, MeOH).

Example 79 5-(1-octynyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

79a. 5-(1-octynyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

A mixture of 5-bromo-6-chloro-3-(1BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (425 mg, 1.1 mmol), 1-octyne (0.2 mL, 1.4 mmol), Pd(PPh)₃ Cl₂ (20 mg), CuI (catalytic amount) and triethylamine (0.5 mL) in methylene chloride (8 mL) was heated at reflux for 16 hours. Heating was continued until no starting material remained. The solvent was removed, and the residue was washed with 10% NaOH then extracted with methylene chloride. The organic extract was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 100:6-100:15 to afford to give the title compound (335 mg, 72% yield). MS (DCI/NH₃) m/z 421 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.48 (s, 9H), 1.49 (m, 2H), 1.62 (m, 2H), 1.88 (m, 2H), 2.00 (m, 2H), 2.48 (m, 2H), 3.34 (m, 2H), 3.90 (m, 1H), 4.12 (m, 2H), 7.30 (br s, 1H), 7.98 (m, 1H).

79b. 5-(1-octynyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 79a was dissolved in TFA (1 ml) and methylene chloride (2 ml), and the solution was stirred at 0° C. for 25 minutes. The solution was warmed to room temperature and made basic with saturated aqueous NaHCO₃. The basic mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 10:5-100:15 to afford to give the free base of the tile compound (126 mg). MS (DCI/NH₃) m/z 321 (M+)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.92 (m, 3H), 1.30 (m, 4H), 2.00 (m, 2H), 2.15 (m, 1H), 2.46 (m, 2H), 2.62 (m, 2H), 2.82 (m, 1H). The base was converted to the salt by treatment with HCl in ether/THF to give the title compound. MS (DCI/NH₃) m/z 321 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 0.93 (m, 3H), 1.26-1.41 (m, 4H), 1.48 (m, 2H), 1.61 (m, 2H), 1.90 (m, 1H), 2.10 (m, 1H), 2.24 (m, 1H), 2.45 (t, J=7.0 Hz, 2H), 3.43 (t, J=7.0 Hz, 2H), 4.09 (m, 1H), 4.21 (m, 1H), 4.34 (dd, J=3.8, 10.3 Hz, 1H), 7.38 (d, J=3.0 Hz, 1H), 8.01 (d, J=2.9 Hz, 1H). Anal. Calcd for C₁₈ H₂₅ N₂ OCl•1.8 HCl: C, 55.94; H, 6.99; N, 7.25. Found: C, 56.05; H, 6.99; N, 6.85. [α]²⁵ _(D) =-3.03° (c 0.76, MeOH).

Example 80 5-(1-octynyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-(1-octynyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 79a (330 mg, 0.78 mmol) was added formalin (37%, 9 mL) and formic acid (4.5 mL), and the mixture was heated at 70° C. for 2 hours. The solvent was concentrated,and solid NaHCO₃ was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:1-100:3 to afford to give the free base of the title compound (166.5 mg (64% yield). MS (DCI/NH₃) m/z 321 (M+)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ0.92 (m, 3H), 1.32 (m, 4H), 1.48 (m, 2H), 1.62 (m, 2H), 1.80 (m, 4H), 2.02 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.47 (s, 3H), 2.66 (m, 1H), 3.12 (m, 1H), 3.93 (m, 2H), 7.27 (m, 1H), 7.98 (m, 1H). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 114°-116° C. (dec). MS (DCI/NH₃) m/z 335 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.02 (t, J=6.7 Hz, 3H), 1.43 (m, 4H), 1.58 (m, 2H), 1.71 (m, 2H), 2.06 (m, 1H), 2.21 (m, 2H), 2.42 (m, 1H, 2.56 (t, J=6.7 Hz, 2H), 3.06 (s, 3H), 3.28 (m, 1H), 3.77 (m, 1H), 3.87 (m, 1H), 4.41 (m, 2H), 7.50 (m, 1H), 8.12 (d, J=2.4 Hz, 1H). Anal. Calcd for C₁₉ H₂₇ N₂ OCl•1.5 HCl: C, 58.58; H, 7.37; N, 7.19. Found: C, 58.64; H, 7.39; N, 7.20. [α]²⁵ _(D) =+8.99° (c 0.64, MeOH).

Example 81 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

80a. 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (1.18 g, 3 mmol), 4-vinylpyridine (0.39 mL, 3.6 mmol), Pd(OAc)₄ (62.5 mg), tris(o-tolyl)phosphine (312.5 mg), and triethylamine (6.25 mL) in acetonitrile (15 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO₃ solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 100:5-100:15 to afford the title compound (852 mg, 69% yield). MS (DCI/NH₃) m/z 416 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.48 (s, 9H), 1.92 (m, 2H), 2.02 (m, 2H), 3.42 (m, 2H), 3.97 (m, 1H), 4.13 (m, 2H), 7.43 (m, 2H), 7.56 (m, 1H), 8.05 (m, 1H), 8.62 (m, 2H).

80b. 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 81a was deprotected and converted to the salt by treatment with HCl in dioxane to give the title compound. MS (DCI/NH₃) m/z 316 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.92-2.07 (m, 1H), 2.09-2.21 (m, 2H), 2.22-2.37 (m, 1H), 3.44 (t, J=6.4 Hz, 2H), 4.15 (m, 1H), 4.31 (dd, J=7.5, 10.6 Hz, 1H), 7.40 (d, J=16.2 Hz, 1H), 7.88 (m, 2H), 8.12 (m, 3H), 8.67 (d, J=7.1 Hz, 2H). Anal. Calcd for C₁₇ H₁₈ N₃ OCl•1.8 HCl: C, 55.94; H, 6.99; N, 7.25. Found: C, 56.05; H, 6.99; N, 6.85. [α]²⁵ _(D) =-2.47° (c 0.77, MeOH).

Example 82 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

To 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 81a (760 mg, 1.8 mmol) was added formalin (37%, 20 mL) and formic acid (10 mL), and the mixture was heated at 100° C. for 1 hours. The solvent was concentrated, and saturated aqueous NaHCO₃ was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO₄ and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:2-100:15 to afford to give the free base of the title compound (327 mg, 55% yield). MS (DCI/NH₃) m/z 330 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.80 (m, 3H), 2.07 (m, 1H), 2.35 (m, 1H), 2.52 (s, 3H), 2.72 (m, 1H), 3.16 (m, 1H), 4.00 (m, 1H), 4.07 (m, 1H), 7.0 (m, 1H), 7.40 (m, 2H), 7.53 (m, 2H), 8.06 (m, 1H), 8.63 (m, 2H). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 220°-222° C. (dec). MS (DCI/NH₃) m/z 330 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 2.06-2.37 (m, 3H), 2.44 (m, 1H), 3.07 (s, 3H), 3.30 (m, 1H), 3.78 (m, 1H), 3.98 (m, 1H), 4.42 (dd, J=6.1, 11.2 Hz, 1H), 4.58 (dd, J=3.0, 11.2 Hz, 1H), 7.35 (d, J=16.3 Hz, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.87 (d, J=3.1 Hz, 1H), 8.03 (d, J=6.8 Hz, 2H), 8.11 (d, J=2.7 Hz, 1H), 8.63 (d, J=6.8 Hz, 2H). Anal. Calcd for C₁₈ H₂₀ N₃ OCl•2.2 HCl: C, 52.73; H, 5.46; N, 10.23. Found: C, 52.98; H, 5.56; N, 9.90. [α]²⁵ _(D) =+11.48° (c 0.30, MeOH).

Example 83 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine trihydrochloride

A sample of 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine from Example 82 (85 mg) was dissolved in methanol. To this solution was added Pd/C (9.5 mg), and the mixture was stirred under H₂ for 16 hours at room temperature. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:3-100:10 to afford to give the free base of the title compound (30 mg). MS (DCI/NH₃) m/z 332 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.65 (m, 2H), 1.80 (m, 1H), 2.0 (m, 1H), 2.32 (m, 1H), 2.47 (s, 3H), 2.64 (m, 1H), 2.96 (m, 4H), 3.12 (m, 1H), 3.90 (m, 3H), 6.98 (m, 1H), 7.12 (m, 2H), 7.96 (m, 1H), 8.50 (m, 2H). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 236°-238° C. MS (DCI/NH₃) m/z 332 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.98-2.23 (m, 3H), 2.38 (m, 1H), 3.01 (s, 3H), 3.17 (m, 2H), 3.25 (m, 3H), 3.74 (m, 1H), 3.90 (m, 1H), 4.27 (dd, J=7.1, 11.2, 1H), 4.44 (dd, J=3.10, 11.2, 1H), 7.36 (d, J=3.0, 1H), 7.70 (d, J=8.4, 2H), 8.01 (d, J=3.0, 1H), 8.56 (d, J=6.1, 2H). Anal. Calcd for C₁₈ H₂₂ N₃ OCl•3 HCl: C, 49.00; H, 5.71; N, 9.52. Found: C, 48.94; H, 5.85; N, 9.23. [α]²⁵ _(D) =+8.64° (c 0.94, MeOH).

Example 84 5-Phenyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

84a. 5-Phenyl-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine

Following the procedure of Example 69b, except substituting 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine from Example 23a for the 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine of step 69b, the title compound was prepared. MS (DCI/NH₃) m/z 390 (M+H)⁺.

84b. 5-Phenyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine

The compound from step 84a was deprotected and converted to the salt by treatment with HCl in ethanol to give the title compound (189 mg, 83% yield). mp 75°-80° C. MS (DCI/NH₃) m/z 289 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₆ H₁₇ N₂ OCl•1.6 HCl: C, 55.53; H, 5.25; N, 7.96. Found: C, 55.53; H, 5.40; N, 8.07. [α]²⁵ _(D) =+9.88° (c 0.27, MeOH).

Example 85 5-(2-thienyl)-6-chloro-3-(2(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

85a. 5-(2-thienyl)-6-chloro-3-(1-BOC-2-pyrrolidinylmethoxy)pyridine

A mixture of 5-bromo-6-chloro-3-(1-BOC-2(R)-pyrrolidinylmethoxy)pyridine from Example 69a (310 mg, 0.87 mmol), 2-thienylboronic acid (167 mg, 1.3 mmol), 2M Na₂ CO₃ (3 mL) and Pd(0) (32 mg) were mixed together in toluene (6 mL), and the mixture was heated at reflux for 4 hours. The mixture was cooled and extracted with chloroform. The CHCl₃ was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate 1:1 to afford the title compound (64 mg, 20% yield). MS (DCI/NH₃) m/z 287 (M+H)⁺. 1 H NMR (CDCl₃, 300 MHz) δ: 1.47 (s, 9H), 1.84-2.11 (m, 3H), 3.31-3.48 (m, 2H), 3.82-4.30 (m, 3H), 7.12 (dd, J=4.5, 6, 1H), 7.34-7.42 (m, 3H), 7.46-7.57 (m, 1H), 8.23 (d, J=3, 1H).

85b. 5-(2-thienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 81a was deprotected by treatment with TFA in methylene chloride to give the free base. MS (DCI/NH₃) m/z 261 (M+H)⁺. 1 H NMR (CDCl₃, 300 MHz) δ: 1.79-2.06 (m, 4H), 2.96-2.22 (m, 2H), 3.55-3.64 (m, 1H), 3.94-4.08 (m, 2H), 7.08-7.13 (m, 1H), 7.32-7.44 (m, 3H), 8.23 (d, J=2 Hz, 1H), 8.49 (m, 1.5 Hz). The free base was converted to the salt with HCl in ethanol to give the title compound (46 mg). mp 178°-180° C. MS (DCI/NH₃) m/z 261 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 1.91-2.06 (m, 1H), 2.07-2.22 (m, 2H), 2.25-2.37 (m, 1H), 3.41-3.46 (m, 2H), 4.14-4.17 (m, 1H), 4.30 (dd, J=2.0, 7.5 Hz, 1H), 4.53 (dd, J=2.4, 10.5 Hz, 1H), 7.23 (dd, J=3.7, 5.1 Hz, 1H), 7.56-7.59 (m, 2H), 7.70-7.71 (m, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.53 (d, J=2 Hz, 1H). Anal. Calcd for C₁₄ H₁₆ N₂ OS•2 HCl•1 H₂ O: C, 47.87; H, 5.74; N, 7.97. Found: C, 47.78; H, 6.13; N, 8.23. [α]²⁵ _(D) =+4.0° (c 0.05, MeOH).

Example 86 5-(2-(4-pyridinyl)vinyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine trihydrochloride

86a. 5-(2-(4-pyridinyl)vinyl)-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

A mixture of 5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine (440 mg, 1.25 mmol), 4-vinylpyridine (0.267 mL), Pd(OAc)₄ (30 mg), tris(o-tolyl)phosphine (160 mg), and triethylamine (3.5 mL) in acetonitrile (4 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO₃ solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ethyl acetate 1:3 to afford the title compound (440 mg, 79% yield). MS (DCI/NH₃) m/z 382 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.49 (s, 3H), 1.85-2.12 (m, 4H), 3/26-3.55 (m, 2H), 3.86-4.08 (m, 1H), 4.08-4.34 (m, 1H), 7.20-7.30 (m, 2H), 7.36-7.42 (m, 2H), 7.71 (br s, 0.5H), 8.22-8.42 (m, 1.5H), 8.58-8.69 (m, 2H).

86b. 5-(2-(4-pyridinyl)vinyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 86a (96 mg) was deprotected to give the free base and the free base was converted to the salt by treatment with HCl in ethanol to give the title compound (75 mg, 77% yield). mp 250°-252° C. MS (DCI/NH₃) m/z 282 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 1.94-2.40 (m, 3H), 3.15-3.24 (m, 1H), 3.46 (t, J=7.5 Hz, 2H), 4.11-4.24 (m, 1H), 4.36-4.44 (m, 1H), 4.58-4.63 (m, 1H), 7.51 (d, J=15.9 Hz, 1H), 7.83 (d, J=16.2 Hz, 1H), 8.10 (br s, 1H), 8.17 (d, J=6.8 Hz, 2H), 8.43 (d, J=3 Hz, 1H), 8.61 (br s, 1H), 8.71 (d, J=6.5 Hz, 1H). Anal. Calcd for C₁₇ H₁₉ N₃ O•3 HCl: C, 52.26; H, 5.67; N, 10.75. Found: C, 51.99; H, 6.00; N, 10.50. [α]²⁵ _(d) =+6.96° (c 0.12, MeOH).

Example 87 5-(2-(4-pyridinyl)ethyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine trihydrochloride

A sample of 5-(2-(4-pyridinyl)vinyl)-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 86a (220 mg) was dissolved in methanol. To the solution was added Pd/C (22 mg), and the mixture was stirred under H₂ for 16 hours at room temperature. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:3-100:10 to afford to give the free base of the title compound (220 mg). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 178°-180° C. MS (DCI/NH₃) m/z 284 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 1.92-2.09 (m, 1H), 2.10-2.17 (m, 2H), 2.20-2.37 (m, 1H), 3.22-3.40 (m, 3H), 3.41 (t, J=7 Hz, 1H), 4.13-4.20 (m, 1H), 4.33 (dd, J=7.4, 10.3 Hz, 1H), 4.53 (dd, J=3.6, 10.6 Hz, 1H), 7.84 (br s, 1H), 7.89 (d, J=6.3 Hz, 2H), 8.20 (br s, 1H), 8.33 (br s, 1H), 8.64 (d, J=6.6 Hz, 2H). Anal. calcd for C₁₇ H₂₁ N₃ O•3.5 HCl: C, 49.68; H, 6.01; N, 10.22. Found: C, 49.67; H, 6.24; N, 10.03. [α]²⁵ _(D) =-2.05° (c 0.26, MeOH).

Example 88 5-(3-aminophenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine trihydrochloride

88a. 5-(3-aminophenyl)-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine

To a solution of 3-aminophenylboronic acid (366 mg, 2.36 mmol, Aldrich Chem. Co.) and 5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-pyridine (560 mg, 1.57 mmol) in toluene (10 mL) was added Pd(0) (58 mg) and Na₂ CO3 (5 mL of a 2M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate and chloroform. The organic extracts were dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate hexane 1:1 to afford to give the title compound (860 mg, 100% yield). MS (DCI/NH₃) m/z 370 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.48 (s, 9h), 1.84-2.13 (m, 4H), 3.28-3.51 (m, 2H), 3.70-4.08 (m, 2H), 4.08-4.29 (m, 2H), 6.70-6.75 (m, 1H), 6.85-7.03 (m, 2H), 7.31-7.50 (m, 2H), 7.50-7.72 (m, 1H), 8.29 (d, J=3.0, 1H), 8.443 (br s, 1H).

88b. 5-(3-aminophenyl)-3-(2(R)-pyrrolidinylmethoxy)pyridine

A sample of the compound from step 88a (300 mg) was stirred in TFA (1.5 mL) and methylene chloride (3.0 mL) for 5 hours at room temperature. The solvent was removed, and the residue was extracted with ethyl acetate. The solution was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate hexane 1:1) to give the free base, and the free base was converted to the salt with HCl in ethanol to afford the title compound (141 mg, 64% yield). mp 240°-242° C. MS (DCI/NH₃) m/z 270 (M+H)+. ¹ H NMR (D₂ O, 300 MHz) δ: 1.97-2.22 (m, 2H), 4.67 (dd, J=3.3, 10.7, 1H), 7.47-7.51 (m, 1H), 7.65-7.75 (m, 4H), 8.32 (dd, J=1.5, 2.6, 1H), 8.54 (d, J=2.5, 1H), 8.72 (d, J=1.5, 1H). Anal. Calcd for C₁₆ H₁₉ N₃ O•3.0 HCl: C, 50.74; H, 5.85; N, 11.10. Found: C, 50.80; H, 5.82; N, 10.88. [α]²⁵ _(D) =+1.38° (c 0.15, MeOH).

Example 89 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine citric acid salt

89a. 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (470 mg, 1.25 mmol) in acetonitrile (6.2 mL) was added 4-vinylpyridine (0.17 mL, 1.57 mmol), palladium acetate (26.0 mg, 0.11 mmol), tri-o-tolylphosphine (130 mg, 0.1 mmol) and triethylamine (2.6 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane 1:1 to 3:1 to afford the title compound (176 mg, 35% yield). MS (CI/NH₃) m/z 402 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.42 (s, 9H), 2.27-2.43 (m, 2H), 3.86-3.95 (m, 2H), 4.27-4.24 (m, 1H), 4.36-4.67 (m, 1H), 4.50-4.60 (m, 1H), 7.07 (d, J=11, 1H), 7.41-7.47 (m, 4H), 7.57 (d, J=11, 1H), 7.58-7.65 (m, 1H), 8.09 (d, J=2, 1H), 8.61-8.68 (m, 2H).

89b. 5-(2-(4-Pyridinyl)vinyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

To a solution of 5-2-(4-Pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 89a (176 mg) in methylene chloride (3 mL) and TFA (1.5 mL) was stirred at room temperature for 3 hours. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with chloroform:methanol:NH₄ OH 10:1:0.1 to afford the free base of the title compound (102 mg, 79% yield). MS (DCI/NH₃) m/z 302 (M+H)⁺. 1 H NMR (CDCl₃, 300 MHz) δ: 2.24-2.48 (m, 2H), 3.42-2.54 (m, 1H), 3.76 (q, J=7.5 Hz, 1H), 4.02-4.17 (m, 2H), 4.26-4.39 (m, 1H), 7.0 (d, J=11.0 Hz, 1H), 7.36-7.44 (m, 2H), 7.52-7.62 (m, 2H), 8.05 (d, J=3.0 Hz, 1H), 8.58-8.73 (m, 2H). The base was treated with HCl in ethanol to afford the hydrochloride salt. mp 195°-197° C. MS (CI/NH₃) m/z 302 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ1.17 (d, J=6, 1H), 2.52-2.66 (m, 2H), 2.68-2.89 (m, 4H), 4.96-5.25 (m, 5H), 6.97-7.12 (m, 1H), 7.33 (d, J=3, 1H), 7.48-7.54 (m, 1H), 7.86-7.95 (m, 1H), 8.04-8.22 (m, 2H), 8.44-8.53 (m, 1H), 8.63-8.71 (m, 1H). Anal. Calcd for C₁₆ H₁₆ N₃ OCl•1.5 C₆ H₈ O₇ •0.5 H₂ O: C, 50.13; H, 4.88; N, 7.01. Found: C, 49.95; H, 4.80; N, 7.31. [α]²⁵ _(D) =-1.14° (c 0.18, MeOH).

Example 90 5-phenyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (370 mg, 1.4 mmol) in 15 mL of THF at 0° C. was added phenylmagnesium bromide (2.8 mL, 2.8 mmol) and (dppp)NiCl2 (4.4 mg, 0.0082 mmol). The mixture was stirred at reflux for 2.5 hours, the quenched by the addition of aqueous ammonium chloride. The aqueous layer was extracted with chloroform. The organic solution was dried, concentrated, and the residue was was purified by chromatography, eluting with 1.5 to 5% methanol in chloroform to afford the free base of the title compound (100 mg, 29% yield). MS (CI/NH₃) m/z 269 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ1.84 (m, 3H), 2.05 (m, 1H), 2.34 (m, 1H), 2.52 (s, 3H), 2.72 (m, 1H), 3.13 (m, 1H), 4.06 (m, 2H), 7.45 (m, 4H), 7.58 (m, 2H), 8.30 (m, 1H), 8.45 (m, 1H). The salt was prepared by treatment with HCl in ether, as described above, to give 55 mg of the title compound. mp 88°-90° C. MS (CI/NH₃) m/z 269 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ2.05-2.26 (m, 3H), 2.44 (m, 1H), 3.28 (m, 1H), 3.78 (m, 1H), 3.95 (m, 1H), 4.45 (dd, J=5.9, 11.0 Hz, 1H), 4.62 (dd, J=2.9, 11.4 Hz, 1H), 7.58 (m, 3H), 7.72 (m, 2H), 7.91 (m, 1H), 8.35 (d, J=2.6 Hz, 1H), 8.56 (d, J=1.5 Hz, 1H), Anal. Calcd for C₁₇ H₂₀ N₂ O•1.9 HCl•0.2Et₂ O: C, 60.66; H, 6.83; N, 7.95. Found: C, 60.73; H, 6.74; N, 7.63. [α]²⁵ _(D) =-10.6° (c 0.66, MeOH).

Example 91 5-(3-thienyl)-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine dihydrochloride

91a. 5-(3-thienyl)-3-(1-BOC-2-(R)-azetdinylmethoxy)pyridine

To a solution of 2-thienylboronic acid (384 mg, 3.0 mmol, Aldrich Chem. Co.) and 5-bromo-3-(1-BOC-2-(R)-azetdinylmethoxy)pyridine (420 mg, 1.2 mmol) in toluene (10 mL) was added Pd(0) (40 mg) and Na₂ CO3 (2 mL of a 2M solution), and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate and chloroform. The organic extracts were dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ethyl acetate 10:1-2:1 to afford to give the title compound (236 mg, 57% yield). MS (DCI/NH₃) m/z 347 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.42 (s, 9H), 2.35 (m, 2H), 3.92 (m, 2H), 4.19 (m, 1H), 4.38 (m, 1H), 4.55 (m, 1H), 7.12 (m, 1H), 7.38 (m, 2H), 7.44 (m 1H), 8.26 (m, 1H), 8.51 (s, 1H).

91b. 5-(3-thienyl)-3-(1-methyl-2-(R)-azetdinylmethoxy)pyridine dihydrochloride

To a sample of the compound from step 91a (122 mg, 0.35 mmol) was added formalin (37%, 4 mL) and formic acid (2 mL), and the mixture was heated at 70° C. for 16 hours. The solvent was concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:5-100:10 to afford to give the free base of the title compound (56 mg, 62% yield). MS (DCI/NH₃) m/z 261 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ2.11 (m, 2H), 2.42 (s, 3H), 2.90 (m, 1H), 3.46 (m, 2H), 4.08 (m, 2H), 7.12 (m, 1H), 7.38 (m, 3H), 8.22 (m, 1H), 8.49 (m, 1H). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 112°-114° C. MS (DCI/NH₃) m/z 261 (M+H)⁺. 1 H NMR (D₂ O, 300 MHz) δ: 2.69 (m, 2H), 3.04 (s, 3H), 4.04 (m, 1H), 4.30 (m, 1H), 4.57 (m, 2H), 4.86 (m, 1H), 7.25 (m, 1H), 7.66 (m, 2H), 8.09 (m, 1H), 8.36 (d, J=2.5 Hz, 1H), 8.67 (d, J=1.5 Hz, 1H). Anal. Calcd for C₁₄ H₁₆ N₂ OS•2.5 HCl•0.8 H₂ O: C, 45.95; H, 5.54; N, 7.66. Found: C, 45.62; H, 5.93; N, 7.88. [α]²⁵ _(D) =-23.94° (c 0.36, MeOH).

Example 92 5-((N-benzoylamino)methyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

92a. 5-Cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To a flamed dried flask purged with nitrogen was added 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (1.84 g, 4.90 mmol) zinc cyanide (0.32 g, 2.70 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.340 g, 0.30 mmol). To the mixture was added degassed DMF (20 mL), and the mixture was heated to 80° C. for 16 hours. The mixture was poured into saturated NaHCO₃ (200 mL), and this mixture was extracted with EtOAc (450 mL), which was dried (MgSO₄) and concentrated. The residue was chromatographed (silica gel; EtOAc/Hexane, 1/4) to afford a colorless oil (0.608 g, 39%). MS (CI/NH₃) m/z 315.00 (M+H⁺), 332.00 (M+H+NH₄ ⁺). ¹ H NMR (CDCl₃, 300 MHz): 1.56 (s, 9H), 2.27-2.32 (m, 2H), 3.80-3.94 (m, 2H), 4.16 (dd, J=2.7, 9.5 Hz, 1H), 4.35-4.42 (m, 1H), 4.49-4.53 (m, 1H), 7.56 (d, J=2.9 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H).

92b. 5-Aminomethyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

5-Cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine (0.26 g, 0.80 mmol) from step 92a was stirred in the presence of Raney nickel (0.047 g, 0.80 mmol) under 1 atm of hydrogen at room temperature for 2 hours. The mixture was filtered, and the solvent was removed to give the title compound.

92c. 5-((N-benzoylamino)methyl)-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To 5-aminomethyl-6-chloro-3-(1-BOC-2-(S)-azetidniylmethoxy)pyridine from step 92b (0.262 g, 0.80 mmol) was added CH₂ Cl₂ (10 mL), triethylamine (0.1619 g, 1.60 mmol) and benzoyl chloride (0.1349 g, 1.0 mmol). The mixture was stirred at room temperature overnight, then concentrated under vacuum. The residue was chromatographed (silica gel; CH₂ Cl₂ /MeOH, 9/1) to afford a light brown foam (0.267 g, 77%). MS (CI/NH₃) m/z 432.00 (M+H⁺), 449.00 (M+NH4⁺). ¹ H NMR (CDCl₃, 300 MHz): 1.57 (s, 9H), 2.25-2.37 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 4.11 (dd, J=2.7, 9.80 Hz, 1H), 4.31-4.39 (m, 1H), 4.49-4.55 (m, 1H), 4.68 (d, J=8.5 Hz, 2H), 6.75 (m, 1H), 7.42-7.56 (m, 4H), 7.79-7.82 (m, 2H), 8.03 (d, J=3.1 Hz, 1H).

92d. 5-((N-benzoylamino)methyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

5-((N-benzoylamino)methyl)-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 92c was dissolved in methylene chloride (10 mL). The mixture was cooled to 0° C., TFA (10 mL) was added and the reaction was stirred for 45 minutes as it warmed to room temperature. The mixture was concentrated in vacuo and taken up in a minimum amount of H₂ O. The aqueous mixture was basified with 15% NaOH and extracted with CH₂ Cl₂ (200 mL), which was dried (MgSO₄) and concentrated. The residue was chromatographed (silica gel; CH₂ Cl₂ /MeOH/NH₄ OH, 90:10:1) to afford a colorless oil (0.101 g, 51%). The isolated free base was taken up in a minimum amount of Et₂ O, cooled to 0° C., and treated with HCl in ethanol to afford the hydrochloride salt. The material was dried overnight under vacuum to afford a white solid (0.124 g). MS (CI/NH₃) m/z: 332.00 (M+H⁺). ¹ H NMR (D₂ O, 300 MHz): 2.60-2.69 (m, 2H), 4.02-4.14 (m, 2H), 4.39 (d, J=6.0 Hz, 2H), 4.64 (s, 2H), 4.82-4.90 (m, 1H), 7.52-7.57 (m, 3H), 7.62-7.67 (m, 1H), 7.80-7.83 (m, 1H), 8.08 (d, J=3.0 Hz, 1H). Anal. Calcd. for C₁₇ H₁₈ N₃ O₂ Cl•1.6HCl•0.40 H₂ O•0.20Et₂ O: C, 51.87; H, 5.48; N, 10.19. Found: C, 51.82; H, 5.44; N, 10.08.

Example 93 5-((N-benzoylamino)methyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine hydrochloride

Following the procedure of Example 91b, substituting 5-((N-benzoylamino)methyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine for the compound of 91a thereof, and carrying the reactions forward as described in Example 91b, the title compound is prepared.

Examples 94-99

Following the procedure of Example 92, replacing the 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine starting material thereof with the starting materials shown in Table xxxxx below, and replacing the benzoyl chloride of step 92c with the acylating reagent shown n Table 2, the desired compounds 94-99 having R² and R⁶ as described in Table 2 are prepared.

                  TABLE 2                                                          ______________________________________                                          ##STR13##                                                                      ##STR14##                                                                     Ex-                                                                            ample n     *      R.sup.2                                                                            Acylating Reagent                                                                           R.sup.3                                    ______________________________________                                         94    1     (R)    F   acetic anhydride                                                                            acetyl                                     95    1     (S)    F   6-chlorohexanoyl                                                                            6-chlorohexanoyl                                                  chloride                                                96    2     (R)    Cl  ethyl formate                                                                               H                                          97    2     (S)    Cl  dimethyl dicarbonate                                                                        methoxyl                                   98    3     (R)    H   furoyl chloride                                                                             furanyl                                    99    3     (S)    H   3-nicotinoyl chloride                                                                       3-pyridyl                                  ______________________________________                                    

Examples 100-105

Following the procedure of Example 92, replacing the 5-bromo-6-chloro-3-(1-methyl-2-(S)-pyridinylmethoxy)pyridine starting material thereof with the starting materials shown in Table xxxxx below, and replacing the benzoyl chloride of step 92c with the acylating reagent shown in Table 3, the desired compounds 100-105 having R² and R⁶ as described in Table 3 are prepared.

                  TABLE 3                                                          ______________________________________                                          ##STR15##                                                                      ##STR16##                                                                     Ex-                                                                            ample n     *      R.sup.2                                                                            Acylating Reagent                                                                            R.sup.3                                   ______________________________________                                         100   1     (R)    F   3-phenylpropionoyl                                                                           2-phenylethyl                                                    chloride                                                101   1     (S)    F   4-chlorobenzoyl                                                                              4-chlorophenyl                                                   chloride                                                102   2     (R)    Cl  3-nitrobenzoyl                                                                               3-nitrophenyl                                                    chloride                                                103   2     (S)    Cl  2-pyrrole-carboxylic                                                                         2-pyrrolyl                                                       acid + EDC                                              104   3     (R)    H   5-nitro-2-furan-                                                                             5-nitrofuranyl                                                   carboxylic acid + EDC                                   105   3     (S)    H   2-pyrazine-carboxylic                                                                        2-pyrazinyl                                                      acid + EDC                                              ______________________________________                                    

Example 106 5-bromo-6-fluoro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

106a. 5-Hydroxy-3-bromo-2-(4-nitrophenylazo)pyridine

5-bromo-3-pyridinol (8.7 g, 0.05 mol) and potassium hydroxide (Fisher Scientific) were dissolved in water (200 ml). A suspension of p-nitrobenzenediazonium tetrafluoroborate (J. Org. Chem., Vol. 44, No. 9. 1979 p 1572-1573) (11.845 g, 0.5 mol) was added, and the mixture was stirred for 1 hour, diluted with acetic acid (50 ml) and filtered. The crude product was allowed to dry in air, then was chromatographed (silica gel; CHCl₃ /MeOH, 95:5 to 90:10) provided 5.45 g (33.7%) of the title compound. MS (DCI/NH₃) m/e 323-325 (M+H)⁺. ¹ H NMR (D₆ DMSO, 300 MHz) δ: 8.48-8.43 (m, 2H), 8.21-8.20 (d, J=2.37 Hz, 1H), 8.09-8.06 (m, 2H), 7.72-7.71 (d, J=2.37 Hz, 1H)

106b. 5-Hydroxy-3-bromo-2-aminopyridine

The compound from step 106a above (5.0 g 15.8 mmol) and tin chloride (Aldrich 25 g, 111 mmol) were suspended in conc. HCl (250 ml) and, methanol (150 ml) and heated to reflux for 1 hour. The mixture was cooled to 0° C. and then filtered. The solution was neutrilized with sodium bicarbonate (180 g) and extracted with ethyl acetate (4×200 ml). The extracts were washed with brine, dried (MgSO₄), and concentrated. The residue was chromatographed (silica gel; CHCl₃ /MeOH/NH₄ OH, 95:5:0.05 to 9:10:1) to afford 3.3 g of the title compound along with substantial amount of tin chloride. MS (DCI/NH₃) m/e 189-191 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ: 7.57-7.56 (d, J=2.6 Hz, 1H), 7.43-7.42 (d, J=2.6 Hz, 1H)

106c. 3-bromo-2-fluoro-5-hydroxypyridine

The compound from step 106b above (3.0 g 15.9 mmol) was dissolved in 50 ml of HF pyridine (Aldrich) and cooled to 0° C. under nitrogen and sodium nitrite (1.09 g 15.8 mmol) was added in portions over 20 min. The reaction was heated to 50° C. for one hour, cooled to 0° C. and then basified with 20% sodium hydroxide. The aqueous phase was washed with methylene chloride (5×100 ml), neutralized with HCl (pH=7), and extracted with ethyl acetate (5×100 ml). These extracts were dried (MgSO₄), filtered, and concentrated in vacuo yielding the title compound as a tan solid. MS (DCI/NH₃) m/e 192-194 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ: 9.38 (d, J=2.6 Hz, 1H), 9.20-9.19 (d, J=2.6 Hz, 1H).

106d. 5-bromo-6-fluoro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine

A sample of 1-BOC-2-(S)-pyrrolidinemethanol, prepared as described above, and of 3-bromo-2-fluoro-5-hydroxypyridine, prepared as in step b above, are reacted with triphenylphosphine and DEAD in THF at room temperature for 16 hours, to give the title compound.

106e. 5-bromo-6-fluoro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The BOC group is removed from the compound of step 106d by treatment with TFA in methylene chloride to give the free base of the title compound. The base is converted to the salt by treatment with hydrogen chloride saturated ethanol. The solvents are removed under vacuum to give the title compound.

Example 107 5-benzoyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

107a. 5-benzoyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyrdine.

The 5-cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine of example 92a in anhydrous ether at 0° C. is treated with 1.5 equivalents of phenylmagnesium bromide in ether and stirring is maintained at 0° to 35° C. until the nitrile is largely consumed. The solvent is evaporated and the residue is treated with 2M aqueous potassium hydrogen sulfate to hydrolyze the intermediate imine. The solution is made basic with potassium carbonate and extracted with ethyl acetate. The combined extracts are dried (Na₂ SO₄) and concentrated to a residue which is chromatographed (silica gel) to afford the title compound.

107b. 5-benzoyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

5-benzoyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 107a is dissolved in methylene chloride (10 mL). The mixture is cooled to 0° C., TFA (10 mL) is added and the reaction is stirred for 45 minutes as it warms to room temperature. The mixture is concentrated in vacuo and taken up in a minimum amount of H₂ O. The aqueous mixture is basified with 15% NaOH and extracted with CH₂ Cl₂ (200 mL), which is dried (MgSO₄) and concentrated. The residue is chromatographed (silica gel) to afford the free amine. The isolated free amine is taken up in a minimum amount of Et₂ O, cooled to 0° C., and treated with HCl in ethanol to afford the hydrochloride salt.

Examples 108-111

Following the procedure of Example 107, replacing the 5-cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine with the starting material compounds shown in Table 3 and replacing the phenylmagnesium bromide reagent thereof with a R⁵ --Mg--Br Grignard reagent or a R⁵ --Li reagent shown in Table 4 below, the desired compounds 108-111 having R² and R⁵ as described in Table 4 are prepared.

                  TABLE 4                                                          ______________________________________                                          ##STR17##                                                                      ##STR18##                                                                     Example n     *       R.sup.2                                                                            R.sup.5 of Reagent                                                                          R.sup.3                                 ______________________________________                                         108     1     (R)     F   n-hexyl      n-hexyl                                 109     1     (S)     Cl  3-quinolinyl 3-quinolinyl                            110     2     (R)     H   2-naphthyl   2-naphthyl                              111     2     (S)     H   4-methyl-1-naphthyl                                                                         4-methyl-1-                                                                    naphthyl                                ______________________________________                                    

Examples 112-117

Following the procedure of Example 107, replacing the 5-cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine with the starting material compounds shown in Table 3 and replacing the phenylmagnesium bromide reagent thereof with a R⁵ --Mg--Br Grignard reagent shown in Table 5 below, the desired compounds 112-117 having R² and R⁵ as described in Table 5 are prepared.

                  TABLE 5                                                          ______________________________________                                          ##STR19##                                                                      ##STR20##                                                                                                R.sup.5 of Grignard                                 Example                                                                               n       *      R.sup.2                                                                             Reagent   R.sup.3                                   ______________________________________                                         112    1       (R)    F    3-pyridinyl                                                                              3-pyridinyl                               113    1       (S)    F    5-pyrimidinyl                                                                            5-pyrimidinyl                             114    2       (R)    Cl   3-pyridazinyl                                                                            3-pyridazinyl                             115    2       (S)    Cl   2-thienyl 2-thienyl                                 116    3       (R)    H    phenylmethyl                                                                             phenylmethyl                              117    3       (S)    H    2-(4-methoxy-                                                                            2-(4-methoxy-                                                        phenyl)ethyl                                                                             phenyl)ethyl                              ______________________________________                                    

Examples 118-121

Following the procedure of Example 18, replacing the styrene starting material thereof with the starting material compounds shown in Table 7, then hydrogenating the product thereof with palladium on charcoal according to the procedure of Example 21 the desired compounds 118-121 having R² and R³ as described in Table 6 are prepared.

                  TABLE 6                                                          ______________________________________                                          ##STR21##                                                                      ##STR22##                                                                     Example                                                                               n     *     R.sup.2                                                                            Starting Material                                                                          R.sup.3                                     ______________________________________                                         118    2     (S)   H   5-carbomethoxy-3-                                                                          2-(5-carbomethoxy-                                                 vinylpyridine                                                                              pyridinyl)ethyl                             119    2     (S)   H   5-bromo-3-  2-(5-bromo-                                                        vinylpyridine                                                                              pyridinyl)ethyl                             120    2     (S)   H   6-amino-5-bromo-3-                                                                         2-(6-amino-5-                                                      vinylpyridine                                                                              bromo-                                                                         pyridinyl)ethyl                             121    2     (S)   H   5-bromo-6-  2-(5-bromo-6-                                                      methylamino-3-                                                                             methylamino-                                                       vinylpyridine                                                                              pyridinyl)ethyl                             ______________________________________                                    

Examples 122-130

Following the procedure of Example 7, replacing the 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine thereof with the starting material compound shown in Table 7 and replacing the 3-pyridinyltributyltin reagent thereof with the reagent shown in Table 7, the desired compounds 122-130 having R² and R³ as described in Table 7 are prepared.

                  TABLE 7                                                          ______________________________________                                          ##STR23##                                                                      ##STR24##                                                                     Ex-                                                                            ample n     *      R.sup.2                                                                            Starting Material                                                                          R.sup.3                                     ______________________________________                                         122   1     (R)    H   5-carbomethoxy-3-                                                                          5-carboxy-3-                                                       pyridinyltributyltin*                                                                      pyridinyl                                   123   1     (S)    H   5-carbomethoxy-3-                                                                          5-formyl-3-pyridinyl                                               pyridinyltri-                                                                  butyltin**                                              124   2     (R)    H   5-hydroxymethyl-3-                                                                         5-hydroxymethyl-3-                                                 pyridinyltributyltin                                                                       pyridinyl                                   125   2     (S)    H   2,4-dimethoxy-5-                                                                           2,4-dimethoxy-5-                                                   pyrimidinyltri-                                                                            pyrimidinyl                                                        butyltin                                                126   3     (R)    H   2-chloro-3- 2-chloro-3-thienyl                                                 thienyltributyltin                                      127   3     (S)    H   2-cyano-3-  2-cyano-3-thienyl                                                  thienyltributyltin                                      128   2     (S)    H   4-methyl-3- 4-methyl-3-thienyl                                                 thienyltributyltin                                      129   2     (S)    H   4-hydroxymethyl-5-                                                                         4-hydroxymethyl-5-                                                 carbomethoxy-3-                                                                            carbomethoxy-3-                                                    thienyltributyltin                                                                         thienyl                                     130   2     (S)    H   4-methoxymethoxy-                                                                          4-methoxymethoxy-                                                  5-carbomethoxy-3-                                                                          5-carbomethoxy-3-                                                  thienyltributyltin                                                                         thienyl                                     ______________________________________                                          *After following the procedures of Example 7, with substitutions as            indicated, the carbomethoxy group is hydrolyzed with base as additional        step in this preparation.                                                      **After following the procedures of Example 7, with substitutions as           indicated, the additional steps are necessary: the carbomethoxy group is       hydrolyzed with base; the resulting free acid is reduced to the alcohol        with LAH, and the resulting alcohol is oxidized to the aldehyde with           Jones' or Collins' reagents.                                             

Examples 131-133

Following the procedure of Example 18, replacing the styrene starting material thereof with the starting material compounds shown in Table 8, then hydrogenating the product thereof with palladium on charcoal according to the procedure of Example 21 the desired compounds 131-133 having R² and R³ as described in Table 8 are prepared.

                  TABLE 8                                                          ______________________________________                                          ##STR25##                                                                      ##STR26##                                                                     Example                                                                               n     *     R.sup.2                                                                            Starting Material                                                                          R.sup.3                                     ______________________________________                                         131    2     (S)   H   4-methyl-3- 2-(4-methyl-3-                                                     vinylbenzene                                                                               phenyl)ethyl                                132    2     (S)   H   4-methoxy-3-                                                                               2-(4-methoxy-3-                                                    vinylbenzene                                                                               phenyl)ethyl                                133    2     (S)   H   4-trifluoromethyl-3-                                                                       2-(4-trifluoromethyl-                                              vinylbenzene                                                                               3-phenyl)ethyl                              ______________________________________                                    

Examples 134-137

Following the procedure of Example 3, replacing the 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine thereof with the starting material compound shown in Table 7 and replacing the 3-methoxyphenylboronic acid reagent thereof with the reagent shown in Table 9, the desired compounds 134-137 having R² and R³ as described in Table 9 are prepared.

                  TABLE 9                                                          ______________________________________                                          ##STR27##                                                                      ##STR28##                                                                     Ex-                                                                            am-                                                                            ple  n     *      R.sup.2                                                                            Reagent      R.sup.3                                     ______________________________________                                         134  1     (R)    H   2-hydroxy-1- 2-hydroxy-1-                                                      naphthylboronic acid                                                                        naphthyl                                    135  1     (S)    H   4'-nitro-4-  4'-nitro-4-biphenyl                                               biphenylboronic acid                                     136  2     (R)    H   4'-fluoro-4- 4'-fluoro-4-biphenyl                                              biphenylboronic acid                                     137  2     (R)    H   4'-methyl-4- 4'-methyl-4-                                                      biphenylboronic acid                                                                        biphenyl                                    ______________________________________                                     

We claim:
 1. A compound having the structure ##STR29## or a pharmaceutically acceptable salt thereof wherein n is selected from 1, 2 or 3;R¹ is selected from the group consisting ofhydrogen, allyl, and alkyl or one to six carbon atoms; R² is selected from the group consisting ofhydrogen, fluorine, chlorine, vinyl, and phenyl; L is absent or is selected from the group consisting ofalkylene of one to six carbon atoms, --C.tbd.C--, .paren close-st.CH═CH.paren close-st._(p) where p is one or two, ##STR30## and ##STR31## where M is selected from --CH₂ --, and --NH--; and R³ is selected from the group consisting of a) hydrogen, b) alkyl of one to six carbon atoms, c) haloalkyl of one to six carbon atoms, d) hydroxyalkyl of one to six carbon atoms, e) alkoxy of one to six carbon atoms, f) amino, g) alkylamino of one to six carbon atoms, h) dialkylamino in which the two alkyl groups are independently of one to six carbon atoms, i) phenyl, j) naphthyl, k) biphenyl l) furyl, m) thienyl, n) pyrazinyl, o) pyridazinyl, p) pyrimidinyl, q) pyrrolyl, r) pyrazolyl, s) imidazolyl, t) indolyl, u) thiazolyl, v) oxazolyl, w) isoxazolyl, x) thiadiazolyl, y) oxadiazolyl, z) quinolinyl, aa) isoquinolinyl, and cc) any of i) through bb) above substituted with one or two substituents independently selected from the group consisting ofalkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl in which the alkoxy and alkyl portions are independently of one to six carbon atoms, alkoxyalkoxyl in which the alkoxy portions are independently of one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms;with the provisos that i) when L is absent, R³ may not be hydrogen, alkyl of one to six carbon atoms, amino, alkylamino or dialkylamino; ii) when L is absent and R³ is hydrogen, R² is selected from vinyl, unsubstituted phenyl, and phenyl substituted as defined in bb) above; and iii) when L is alkylene, R³ may not be hydrogen of alkyl; iv) when L is ##STR32## then R³ is selected from alkyl of one to six carbon atoms, i), j), l), m), n), q), r), and bb) as defined above, and any of i), j), l), m), n), q), r) and bb) as substituted as defined in cc) above; v) when L is ##STR33## and M is --CH₂ --, then R³ may not be hydrogen; and vi) f) through y) above may be substituted as defined in z) above by no more than one alkylamino, carboxyl, or alkoxycarbonyl substituent.
 2. A compound according to claim 1 wherein n is
 1. 3. A compound according to claim 1 wherein n is
 2. 4. A compound according to claim 1 wherein n is
 3. 5. A compound according to claim 2 selected from the group consisting of:5-methyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine; 5-phenyl-3-(2-(S)-azetidinylmethoxy)pyridine; 5-phenyl-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(1-hexynyl)-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(2-(4pyridinyl)vinyl)-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(2-(4pyridinyl)ethyl)-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(2-(4pyridinyl)vinyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(2-(4pyridinyl)ethyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(1-octynyl)-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(1-octynyl)-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(3-aminophenyl)-3-(2-(S)-azetidinylmethoxy)pyridine; 5-bromo-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-phenyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-phenyl-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(2-(4pyridinyl)vinyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(3-thienyl)-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine; 5-((N-benzoylamino)methyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(benzamidomethyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(acetamidomethyl)-6-chloro-3-(2-(R)-azetidinylmethoxy)pyridine; 5-(6-chlorohexanamidomethyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(3-phenylpropionamidomethyl)-6-chloro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine; 5-(6-chlorobenzamidomethyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-benzoyl-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-hexanoyl-6-chloro-3-(2-(R)-azetidinylmethoxy)pyridine; 5-(3-quinolinoyl)-6-chloro-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(3-nicotinyl)-6-chloro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine; 5-(5-pyridinecarbonyl)-6-chloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine; 5-(5-carboxy-3-pyridinyl)-3-(2-(R)-azetidinylmethoxy)pyridine; 5-(5-formyl-3-pyridinyl)-3-(2-(S)-azetidinylmethoxy)pyridine; 5-(2-hydroxy-1-naphthyl)-3-(2-(R)-azetidinylmethoxy)pyridine; and 5-(4'-nitro-4-biphenyl)-3-(2-(S)-azetidinylmethoxy)pyridine;or a pharmaceutically acceptable salt thereof.
 6. A compound according to claim 3 selected from the group consisting of:5-(3-nitrophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(1-naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-methoxyphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-hexynyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-furanyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-thienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-pyridyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-vinyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(1-decynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-acetyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-hexyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(5-cyano-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(methoxycarbonyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine 5-(2-(methoxycarbonyl)ethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(5-phenyl-1-pentynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-trans-(2-phenylethenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(1-pyrrolidinylcarbonyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-chlorophenyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-phenylethyl))-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-oxo-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(5-pyrimidinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-phenyl-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-methoxycarbonyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(6-hydroxy-1-hexenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)ethyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine trihydrochloride; 5-(5,5-dimethyl-1,3-hexadienyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-naphthalenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-acetyl-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)ethylenyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-pyridinyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-quinolinyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(1-methyl-2-indolyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3,5-bis(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-chlorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2,4-dichlorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-phenylethynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-methylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-chloro-4-fluorophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-aminophenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-formylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-methylphenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-(trifluoromethyl)phenyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3,3-dimethylbutynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-methylphenyl)ethynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(1-octynyl)-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)ethylenyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-phenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-phenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-phenyl-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-phenyl-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5,6-diphenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5,6-diphenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-bromo-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-bromo-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(3-aminophenyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(4-chlorophenyl)-6-chloro-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(1-octynyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(1-octynyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)ethyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-phenyl-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-thienyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)vinyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-pyridinyl)ethyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(3-aminophenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-phenyl-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(formamidomethyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-((N-methoxycarbonylamino)methyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(3-nitrobenzamidomethyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-((N-2-pyrrolycarbonylamino)methyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-bromo-6-fluoro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-naphthoyl)-6-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(4-methyl-1-naphthoyl)-6-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine; methoxy)pyridine; 5-(3-pyridazinecarbonyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2-thiophenecarbonyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(5-carbomethoxypyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(5-bromopyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(6-amino-5-bromopyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(5-bromo-6-methylaminopyridinyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(5-hydroxymethyl-3-pyridinyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(2,4-dimethoxy-5-pyrimidinyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-methyl-3-thienyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; 5-(4-hydroxymethyl-5-carbomethoxy-3-thienyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4-methoxymethoxy-5-carbomethoxy-3-thienyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-methyl-3-phenyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-methoxy-3-phenyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(2-(4-trifluoromethyl-3-phenyl)ethyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 5-(4'-fluoro-4-biphenyl)-3-(2-(R)-pyrrolidinylmethoxy)pyridine; and 5-(4'-methyl-4-biphenyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine;or a pharmaceutically acceptable salt thereof.
 7. A compound according to claim 4 selected from the group consisting of:5-(furamidomethyl)-6-chloro-3-(2-(R)-piperidinylmethoxy)pyridine; 5-(nicotinamidomethyl)-6-chloro-3-(2-(S)-piperidinylmethoxy)pyridine; 5-(5-nitro-2-furamidomethyl)-6-chloro-3-(1-methyl-2-(R)-piperidinylmethoxy)pyridine; 5-((N-2-pyrazincarbonylamino)methyl)-6-chloro-3-(1-methyl-2-(S)-piperidinylmethoxy)pyridine; 5-(2-phenylacetyl)-6-chloro-3-(1-methyl-2-(R)-piperidinylmethoxy)pyridine; 5-(3-(4-methoxyphenyl)propionyl)-6-chloro-3-(1-methyl-2-(S)-piperidinylmethoxy)pyridine; 5-(2-chloro-3-thienyl)-3-(2-(R)-piperidinylmethoxy)pyridine; and 5-(2-cyano-3-thienyl)-3-(2-(S)-piperidinylmethoxy)pyridine;or a pharmaceutically acceptable salt thereof.
 8. A pharmaceutical composition for selectively controlling synaptic transmission, comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a compound according to claim
 1. 9. A method for selectively controlling synaptic transmission comprising administering to a host mammal in need of such treatment a therapeutically-effective amount of a compound according to claim
 1. 